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Use of Sacubitril/Valsartan Prior to Primary Prevention Implantable Cardioverter Defibrillator Implantation.

  • Daniel Ozier
    Affiliations
    Temetry School of Medicine, University of Toronto, Toronto, Ontario, Canada

    Schulich Heart Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
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  • Talha Rafiq
    Affiliations
    Medical Sciences Graduate Program, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
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  • Russell de Souza
    Affiliations
    Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada

    Population Health Research Institute, Hamilton Health Sciences Corporation, Hamilton, ON, Canada
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  • Sheldon M. Singh
    Correspondence
    Corresponding author: Sheldon Singh, MD, A222, 2075 Bayview Avenue, Toronto, Ontario, Canada, M3N 3M5, , Tel: 416 480 6100 x 83659, Fax: 416 480 5707
    Affiliations
    Temetry School of Medicine, University of Toronto, Toronto, Ontario, Canada

    Schulich Heart Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
    Search for articles by this author
Open AccessPublished:October 14, 2022DOI:https://doi.org/10.1016/j.cjco.2022.10.005

      Abstract:

      Background

      Implantable cardioverter defibrillators (ICDs) are an adjunct to guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF). The uptake of sacubitril/valsartan in this population is not well described. We report the uptake and factors associated with sacubitril/valsartan use in patients with left ventricular dysfunction undergoing ICD implantation.

      Methods

      A retrospective chart review was performed on all patients with left ventricular dysfunction who underwent de novo primary prevention ICD implantation between October 2015 and December 2021 (n=422) at Sunnybrook Health Sciences Center, Toronto, Ontario, Canada. Pre-procedure sacubitril/valsartan use was determined. Logistic regression analysis was performed to examine factors associated with sacubitril/valsartan use. A Bayesian estimator of abrupt change was employed to determine a time period where a change in the rate of sacubitril/valsartan use occurred.

      Results

      Loop diuretic use (Odds Ratio [OR]=2.20) and higher severity of New York Heart Association (NYHA) class symptoms (OR=1.62) were associated with sacubitril/valsartan use. Sacubitril/valsartan use increased during the study period to 59% in December 2021. This increase was larger amongst those ≥65 years (OR=1.09). A change in the rate of sacubitril/valsartan use occurred 3 years after drug approval, 1 year after provincial drug coverage became available and 6 months after strong recommendations in clinical guidelines.

      Conclusions

      In a contemporary cohort of ICD patients sacubitril/valsartan use increased between 2015 and 2021, notably in those ≥65 years and after the availability of government drug coverage. Understanding barriers to sacubitril/valsartan use in ICD patients is recommended to improve clinical outcomes and survival in this population.

      Graphical abstract

      Keywords

      INTRODUCTION:

      The implantable cardioverter defibrillator (ICD) is an important adjunct to guideline-directed medical therapies (GDMT) in patients with heart failure and a reduced ejection fraction (HFrEF)
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      • Parkash R.
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      Canadian cardiovascular society/Canadian heart rhythm society 2016 implantable cardioverter-defibrillator guidelines.
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      • et al.
      comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure.
      with pivotal clinical trials demonstrating a reduction in sudden cardiac death and improvement in overall survival
      • Moss A.J.
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      • Hall W.J.
      • Klein H.
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      • et al.
      Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
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      Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.
      . A dramatic increase in the armamentarium of drugs comprising GDMT has occurred since the publication of initial landmark ICD trials
      • McDonald M.
      • Virani S.
      • Chan M.
      • Ducharme A.
      • Ezekowitz J.A.
      • Giannetti N.
      • et al.
      CCS/CHFS heart failure guidelines update: Defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      .
      Sacubitril/valsartan is a newer HF therapy currently considered a pillar in the treatment of HFrEF. In 2014 the Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure (PARADIGM-HF) trial demonstrated a 2.8% absolute reduction for HF hospitalization and a 2.8% improvement in overall survival in HF patients, compared to standard medical therapy
      • McMurray J.J.V.
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      • Desai A.S.
      • Gong J.
      • Lefkowitz M.P.
      • Rizkala A.R.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      . The benefits of sacubitril/valsartan extended to patients regardless of age, severity of left ventricular (LV) dysfunction, and presence of ICDs
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      • Packer M.
      • Desai A.S.
      • Gong J.
      • Lefkowitz M.P.
      • Rizkala A.R.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      • Rohde L.E.
      • Chatterjee N.A.
      • Vaduganathan M.
      • Claggett B.
      • Packer M.
      • Desai A.S.
      • et al.
      Sacubitril/valsartan and sudden cardiac death according to implantable cardioverter-defibrillator use and Heart Failure cause: A PARADIGM-HF analysis.
      . In 2014 the Canadian Cardiovascular Society (CCS) HF Management Focused Update provided a conditional recommendation on sacubitril/valsartan use
      • Moe G.W.
      • Ezekowitz J.A.
      • O’Meara E.
      • Lepage S.
      • Howlett J.G.
      • Fremes S.
      • et al.
      The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: anemia, biomarkers, and recent therapeutic trial implications.
      . Health Canada approval was granted in October 2015

      Government of Canada, Health Canada, Health Products, Food Branch. Summary Basis of Decision - Entresto - Health Canada [Internet]. The Drug and Health Product Register, Government of Canada. 2015 [cited 2022 May 23]. Available from: https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00208

      . Coverage under the Ontario Drug Benefit plan (which provides drug coverage for Ontarians ≥65 years of age) was obtained in April 2017

      Ministry of Health and Long-Term Care. Ontario Drug Benefit Formulary/Comparative Drug Index Edition 42 Summary of Changes – April 2017 [Internet]. 2017 Apr [cited 2022 May 23]. Available from: https://www.health.gov.on.ca/en/pro/programs/drugs/formulary42/summary_edition42_20170420

      . Recommendations on sacubitril/valsartan use were further expanded upon and upgraded to a “strong” recommendation in the 2017 CCS HF guidelines
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • Abrams H.
      • Chan M.
      • Ducharme A.
      • et al.
      comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure.
      and additional evidence on its safety was provided with the publication of the Angiotensin-Neprilysin Inhibition in Acute Decompensated HF (PIONEER-HF) trial in 2019
      • Velazquez E.J.
      • Morrow D.A.
      • DeVore A.D.
      • Duffy C.I.
      • Ambrosy A.P.
      • McCague K.
      • et al.
      Angiotensin-neprilysin inhibition in acute decompensated heart failure.
      .
      Clinical guidelines for ICD implantation state all patients undergoing ICD implantation require at least 3 months of optimal medial therapy, however are not explicit as to what constitutes optimal medical therapy.
      • Bennett M.
      • Parkash R.
      • Nery P.
      • Sénéchal M.
      • Mondesert B.
      • Birnie D.
      • et al.
      Canadian cardiovascular society/Canadian heart rhythm society 2016 implantable cardioverter-defibrillator guidelines.
      One would hypothesize that a large proportion of patients undergoing ICD implantation should receive sacubitril/valsartan prior to ICD implantation as sacubitril/valsartan use was recommended for patients with a reduced EF and symptoms of heart failure. This hypothesis would be bolstered by the fact that sacubitril/valsartan has important benefits in ICD candidates including an improvement in EF such that some individuals no longer meet EF-based criteria for ICDs
      • Guerra F.
      • Ammendola E.
      • Ziacchi M.
      • Aspromonte V.
      • Pellegrino P.L.
      • Del Giorno G.
      • et al.
      Effect of SAcubitril/Valsartan on left vEntricular ejection fraction and on the potential indication for Implantable Cardioverter Defibrillator in primary prevention: the SAVE-ICD study.
      and is also associated with a reduction in the risk of ventricular arrhythmia and subsequent ICD therapies.
      • Rohde L.E.
      • Chatterjee N.A.
      • Vaduganathan M.
      • Claggett B.
      • Packer M.
      • Desai A.S.
      • et al.
      Sacubitril/valsartan and sudden cardiac death according to implantable cardioverter-defibrillator use and Heart Failure cause: A PARADIGM-HF analysis.
      ,
      • de Diego C.
      • González-Torres L.
      • Núñez J.M.
      • Centurión Inda R.
      • Martin-Langerwerf D.A.
      • Sangio A.D.
      • et al.
      Effects of angiotensin-neprilysin inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices.
      As sacubitril/valsartan is a newer HF therapy, its uptake, and factors associated therewith, in patients undergoing ICD implantation are not well defined
      • Salimian S.
      • Deyell M.W.
      • Andrade J.G.
      • Chakrabarti S.
      • Bennett M.T.
      • Krahn A.D.
      • et al.
      Heart failure treatment in patients with cardiac implantable electronic devices: Opportunity for improvement.
      . Given the specific benefits of sacubitril/valsartan in ICD patients
      • Rohde L.E.
      • Chatterjee N.A.
      • Vaduganathan M.
      • Claggett B.
      • Packer M.
      • Desai A.S.
      • et al.
      Sacubitril/valsartan and sudden cardiac death according to implantable cardioverter-defibrillator use and Heart Failure cause: A PARADIGM-HF analysis.
      ,
      • Guerra F.
      • Ammendola E.
      • Ziacchi M.
      • Aspromonte V.
      • Pellegrino P.L.
      • Del Giorno G.
      • et al.
      Effect of SAcubitril/Valsartan on left vEntricular ejection fraction and on the potential indication for Implantable Cardioverter Defibrillator in primary prevention: the SAVE-ICD study.
      ,
      • de Diego C.
      • González-Torres L.
      • Núñez J.M.
      • Centurión Inda R.
      • Martin-Langerwerf D.A.
      • Sangio A.D.
      • et al.
      Effects of angiotensin-neprilysin inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices.
      , this knowledge may identify a care gap and improve the clinical care of a well-defined, high-risk patient population with LV dysfunction. Furthermore, study into the uptake of this novel HF agent will provide insight as to whether past practices of delayed uptake of evidence based cardiovascular therapies
      • Anderson T.S.
      • Lo-Ciganic W.-H.
      • Gellad W.F.
      • Zhang R.
      • Huskamp H.A.
      • Choudhry N.K.
      • et al.
      Patterns and predictors of physician adoption of new cardiovascular drugs.
      continue to exist, and specifically examine this in a cohort of patients receiving a costly non-pharmacologic/device therapy. Herein we report the uptake of, and factors associated with, the use of sacubitril/valsartan in patients with HFrEF undergoing primary-prevention ICD implantation.

      METHODS:

      Sunnybrook Health Sciences Centre (SHSC) is a large regional tertiary cardiac care centre in Toronto, Ontario, Canada. All patients undergoing de novo ICD implantation for primary prevention between October 1st 2015 and December 31st 2021 were included in this single-center retrospective study. Patients undergoing ICD implantation during an inpatient admission were excluded as they may not have had the opportunity to receive evidence-based heart failure therapies prior to ICD implantation. Patients with an EF>35%, a known history of an inherited arrhythmia (e.g. long QT, Brugada, hypertrophic cardiomyopathy) or other cardiomyopathy (e.g. sarcoidosis, muscular dystrophy) were excluded due to a lack of evidence for sacubitril/valsartan use in these populations. Given the lack of reliability amongst practitioners in assigning NYHA class
      • Stamp K.D.
      • Prasun M.A.
      • McCoy T.P.
      • Rathman L.
      Providers’ assignment of NYHA functional class in patients with heart failure: A vignette study.
      and overlap in classification of NYHA I/II class
      • Yap J.
      • Lim F.Y.
      • Gao F.
      • Teo L.L.
      • Lam C.S.P.
      • Yeo K.K.
      Correlation of the New York Heart Association classification and the 6-minute walk distance: A systematic review.
      , the primary analysis included all patients with NYHA I-IV symptoms. A sensitivity analysis limited to patients with NYHA II-IV symptoms was performed as the CCS HF guidelines recommended sacubitril/valsartan with HF symptoms
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • Abrams H.
      • Chan M.
      • Ducharme A.
      • et al.
      comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure.
      .
      Hospital (Sunnycare version 7.5.4.4; Sovera version 10.4.1) and ICD clinic (Paceart Optima System, version 1.8.269.0, Medtronic, Minneapolis, MN) electronic medical records were reviewed for each patient to determine demographics, clinical characteristics, and details of the implanted device. Medication use, electrocardiographic characteristics, resting heart rate and blood pressure was obtained at the day of implantation. Biochemical data was determined with pre-procedure blood work performed no earlier than 3 months prior to the procedure date.
      Descriptive statistics including mean and standard deviation (SD) for continuous variables and frequency and percentage for categorical variables were reported for patients that received sacubitril/valsartan prior to ICD insertion and those who did not.
      A multivariable binary logistic regression model was fitted to identify independent predictors of sacubitril/valsartan use. Variables in the model included patient clinical characteristics and medication use. The time period an individual was included in the study (expressed per 3 months of the study period) was included as a variable in the model as it is well known that time from approval of a drug is associated with its uptake
      • Anderson T.S.
      • Lo-Ciganic W.-H.
      • Gellad W.F.
      • Zhang R.
      • Huskamp H.A.
      • Choudhry N.K.
      • et al.
      Patterns and predictors of physician adoption of new cardiovascular drugs.
      ,
      • Medlinskiene K.
      • Tomlinson J.
      • Marques I.
      • Richardson S.
      • Stirling K.
      • Petty D.
      Barriers and facilitators to the uptake of new medicines into clinical practice: a systematic review.
      ,
      • Hanney S.R.
      • Castle-Clarke S.
      • Grant J.
      • Guthrie S.
      • Henshall C.
      • Mestre-Ferrandiz J.
      • et al.
      How long does biomedical research take? Studying the time taken between biomedical and health research and its translation into products, policy, and practice.
      . Furthermore, because government-funded drug coverage for sacubitril/valsartan became available during the study period for those patients ≥65 years, a “time by age” interaction term was also included in the model to assess whether the influence of time on the odds of sacubitril/valsartan prescription was influenced by age (or vice-versa). Odds ratio (OR), 95% confidence intervals (95% CI), and p-values were reported, and statistical analysis was conducted at a significance level of 0.05 for a two-tail test using SAS software version 9.4 (SAS Institute Inc., Cary, North Carolina, USA).
      A Bayesian Estimator of Abrupt change, Seasonality, and Trend (BEAST) was used to capture trends and abrupt changes in the rate of sacubitril/valsartan use during the study period in order to provide context to the impact of specific milestones (i.e. guidelines recommendations, availability of government drug coverage) on a change in the prescription of sacubitril/valsartan. The mathematical details of BEAST have been described in detail previously
      • Zhao K.
      • Wulder M.A.
      • Hu T.
      • Bright R.
      • Wu Q.
      • Qin H.
      • et al.
      Detecting change-point, trend, and seasonality in satellite time series data to track abrupt changes and nonlinear dynamics: A Bayesian ensemble algorithm.
      . Briefly, BEAST combines several models into an average model (Bayesian model average) instead of relying on a single model to detect changes in time series. It allows for estimation of the probability for abrupt changes at any given point in time as opposed to other change point algorithms that simply identify whether there is a change point or not (binary result). The BEAST modeling of receiving sacubitril/valsartan in the 3-month time series was performed using the package “Rbeast” v0.9.3 in R software v1.2.5.
      Ethics approval was obtained from the Sunnybrook Health Sciences Centre Research Ethics Board.

      RESULTS:

      This study included 422 patients (mean age = 68, SD = 12 years, 80% male). Of the 130 patients on patients on sacubitril/valsartan, 57 (44%) received a low (24/26mg), 37 (28%) a medium (49/51mg), and 36 (28%) a high dose (97/103mg). In total, 59% of the cohort had a prior history of coronary artery disease, and 78% had at least one year of LV dysfunction. Beta-blockers were used by 93% of patients. Angiotensin Converting Enzyme inhibitors (ACEi), Angiotensinogen Receptor Blockers (ARB) or sacubitril/valsartan were used in 89% of patients. Mineralocorticoid Receptor Antagonists (MRA) were used by 44% of patients. Patients receiving sacubitril/valsartan more frequently had a non-ischemic etiology of HF, lower mean EF, and wider baseline QRS. They reported higher rates of New York Heart Association (NYHA) ≥ 2 symptoms, were more frequent users of loop diuretics and MRAs and received a higher proportion of biventricular defibrillators (Table 1). Sacubitril/valsartan use increased during the study period from 0% in 2015 to 59% in 2021, with 50% of patients <65 and 61% of patients ≥65 years receiving sacubitril/valsartan in 2021.
      Table 1Baseline characteristics
      VariablesSacubitril/Valsartan (Yes), (n = 130)Sacubitril/Valsartan (No), (n = 292)p-value
      Age (years), mean (SD)68.4 (11.8)68.2 (11.4)0.83
      Gender (Female), n (%)32 (24.6)52 (17.8)0.11
      Prior MI Ischemic CM (Yes), n (%)61 (46.9)187 (64.0)0.001
      AF (Yes), n (%)37 (28.5)89 (30.5)0.68
      Severity of EF, mean (SD)26.0 (6.2)27.3 (5.4)0.04
      Severity of CHF symptoms (NYHA), n (%)<.0001
       118 (13.9)105 (36.3)
       288 (67.7)122 (42.2)
       324 (18.5)62 (21. 5)
      Hypertension (Yes), n (%)88 (67.7)188 (64.4)0.51
      Systolic blood pressure (mmHg), mean (SD)123.8 (19.6)125.1 (17.5)0.49
      Creatinine clearance, mean (SD)71.8 (32.7)70.5 (37.3)0.74
      Loop Diuretic (Yes), n (%)94 (72.3)159 (54.5)0.0005
      Device Type, n (%)

      BiV

      Non BiV
      70 (53.9)

      60 (46.2)
      105 (36.0)

      187 (64.0)
      0.0006
      Duration of LV dysfunction ≥1 Year (Yes), n (%)105 (80.8)224 (76.7)0.35
      QRS Duration (msec), mean (SD)147.0 (30.9)133.2 (29.7)<.0001
      Potassium, mean (SD)4.4 (0.5)4.4 (0.5)0.93
      Beta-Blocker (Yes), n (%)124 (95.4)268 (91. 8)0.18
      MRA (Yes), n (%)75 (57.7)111 (38.0)0.0002
      Digoxin (Yes), n (%)5 (3.9)15 (5.1)0.56
      ACEi/ARB (Yes), n (%)0 (0)247 (84.6)<.0001
      MI = myocardial infarction; CM = cardiomyopathy; AF = atrial fibrillation; EF = ejection fraction; CHF = congestive heart failure; NYHA = New York Heart Association; BiV = Biventricular; LV = Left Ventricle; MRA = mineralocorticoid receptor antagonist; ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker
      The results from multivariable analysis examining the factors associated with sacubitril/valsartan use in patients undergoing de novo primary prevention ICD implantation are presented in Table 2. In comparison to patients not on loop diuretics, patients receiving loop diuretics had 2.20 higher odds (95% CI = 1.20-4.04) of sacubitril/valsartan use. Patients with higher NYHA class (OR=1.62; 95% CI=1.01-1.19) were more likely to be prescribed sacubitril/valsartan and those with a history of atrial fibrillation were less likely to be prescribed sacubitril/valsartan (OR=0.48; 95% CI=0.26-0.90). When examining change in use of sacubitril/valsartan over time, on average, sacubitril/valsartan use increased over the study period (OR=1.13 per 3-month interval; 95% CI=1.06-1.20). Furthermore, a two-way interaction was found between time and age of patients suggesting that the increasing use of sacubitril/valsartan over the study period was higher in patients ≥65 years of age compared to those <65 years (OR per 3-month interval:1.09; 95% CI=1.01-1.19; Figure 1).
      Table 2Factors associated with Sacubitril/valsartan use
      VariablesOdds Ratio95% CIp-value
      Time (3-month intervals)1.131.06, 1.200.0001
      Age (≥65 vs. <65 years)0.330.08, 1.310.12
      Time (3-month intervals) and Age (≥65 years)1.091.01, 1.190.03
      Gender (Females vs. Males)1.100.56, 2.160.79
      Prior MI Ischemic CM (Yes vs. No)0.610.34, 1.080.09
      AF (Yes vs. No)0.480.26, 0.900.02
      Severity of EF0.960.92, 1.000.07
      Severity of CHF symptoms (NYHA)1.621.06, 2.450.02
      Systolic blood pressure (mmHg)1.010.99, 1.020.53
      Creatinine clearance1.011.00, 1.010.13
      Loop Diuretic (Yes vs. No)2.201.20, 4.040.01
      Device Type (BiV vs. non BiV)1.580.91, 2.750.10
      Duration of LV dysfunction ≥1 Year (Yes vs. No)1.840.96, 3.510.07
      MRA (Yes vs. No)1.680.97, 2.910.07
      MI = myocardial infarction; CM = cardiomyopathy; AF = atrial fibrillation; EF = ejection fraction; CHF = congestive heart failure; NYHA = New York Heart Association; BiV = Biventricular; LV = Left Ventricle; MRA = mineralocorticoid receptor antagonist
      Figure thumbnail gr1
      Figure 1Probability of Sacubitril/valsartan use during the study period stratified by age PARADIGM-HF: Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure
      • McMurray J.J.V.
      • Packer M.
      • Desai A.S.
      • Gong J.
      • Lefkowitz M.P.
      • Rizkala A.R.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      ; CCS HF Update 1: Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update
      • Moe G.W.
      • Ezekowitz J.A.
      • O’Meara E.
      • Lepage S.
      • Howlett J.G.
      • Fremes S.
      • et al.
      The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: anemia, biomarkers, and recent therapeutic trial implications.
      ; Health Canada NOC: Health Canada Notice of Compliance for Sacubitril/valsartan, Oct 2nd, 2015

      Government of Canada, Health Canada, Health Products, Food Branch. Summary Basis of Decision - Entresto - Health Canada [Internet]. The Drug and Health Product Register, Government of Canada. 2015 [cited 2022 May 23]. Available from: https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00208

      ; ODB Coverage: Ontario Drug Benefits addition of Sacubitril/valsartan to provincial formula, Apr 27th, 2017

      Ministry of Health and Long-Term Care. Ontario Drug Benefit Formulary/Comparative Drug Index Edition 42 Summary of Changes – April 2017 [Internet]. 2017 Apr [cited 2022 May 23]. Available from: https://www.health.gov.on.ca/en/pro/programs/drugs/formulary42/summary_edition42_20170420

      ; CCS HF Update 2: Comprehensive Update of the CCS Guidelines for the Management of Heart Failure
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • Abrams H.
      • Chan M.
      • Ducharme A.
      • et al.
      comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure.
      ; PIONEER-HF: Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure
      • Velazquez E.J.
      • Morrow D.A.
      • DeVore A.D.
      • Duffy C.I.
      • Ambrosy A.P.
      • McCague K.
      • et al.
      Angiotensin-neprilysin inhibition in acute decompensated heart failure.
      ;CCS HF Update 3: CCS/Canadian Heart Failure Society Guidelines Update: Defining a New Pharmacologic Standard of Care for HFrEF
      • McDonald M.
      • Virani S.
      • Chan M.
      • Ducharme A.
      • Ezekowitz J.A.
      • Giannetti N.
      • et al.
      CCS/CHFS heart failure guidelines update: Defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      . X: denotes results of Bayesian change-point analysis which revealed a statistically significant change in the probability of receiving Sacubitril/valsartan occurred during the 3-month segment from April 1st-June 30th, 2018.
      Using the BEAST model, a change point in the probability of being prescribed sacubitril/valsartan was detected during the 3-month interval between April 1st and June 30th, 2018 (Figure 1). This time point was approximately 3 years after drug approval, 1 year from the availability of provincial drug coverage, and 6 months after strong recommendations in clinical guidelines.
      A sensitivity analysis limiting the cohort to individuals with NYHA II-IV symptoms (n=299) was performed (see Supplemental Appendix). Sacubitril/valsartan use increased during the study period with 67% of this subgroup receiving sacubitril/valsartan in 2021 - 64% of patients <65 and 68% of patients ≥65 years. Similar findings as reported above were observed when the cohort was limited to patients with NYHA II-IV symptoms although, as expected with the reduced sample size, statistical significance of some findings was no longer demonstrable.

      DISCUSSION:

      This single-centre, retrospective cohort study described the factors associated with sacubitril/valsartan use in patients undergoing primary prevention ICD implantation. Several important findings are demonstrated in this work. First, increased use of sacubitril/valsartan occurred well after the publication of its landmark clinical trial, recommendations within guidelines, and availability of provincial drug coverage. Second, although clinical factors reflecting symptomatic heart failure were strongly associated with sacubitril/valsartan prescription, non-clinical factors including time from availability and age ≥65, both reflecting the impact of access to provincial drug coverage, were important predictors of sacubitril/valsartan use.
      Our findings are consistent with prior work from various jurisdictions demonstrating suboptimal uptake of GDMT in HFrEF patients
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      • Dunlay S.M.
      Adoption of sacubitril/valsartan for the management of patients with heart failure.
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      Use of guideline-directed medications for heart failure before cardioverter-defibrillator implantation.
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      • et al.
      Medical therapy for Heart Failure with reduced ejection fraction: The CHAMP-HF registry.
      • Huitema A.A.
      • Daoust A.
      • Anderson K.
      • Poon S.
      • Virani S.
      • White M.
      • et al.
      Optimal usage of sacubitril/valsartan for the treatment of heart failure: The importance of optimizing heart failure care in Canada.
      , and a delay in uptake of pharmacologic therapies in general
      • Anderson T.S.
      • Lo-Ciganic W.-H.
      • Gellad W.F.
      • Zhang R.
      • Huskamp H.A.
      • Choudhry N.K.
      • et al.
      Patterns and predictors of physician adoption of new cardiovascular drugs.
      ,
      • Medlinskiene K.
      • Tomlinson J.
      • Marques I.
      • Richardson S.
      • Stirling K.
      • Petty D.
      Barriers and facilitators to the uptake of new medicines into clinical practice: a systematic review.
      • Hanney S.R.
      • Castle-Clarke S.
      • Grant J.
      • Guthrie S.
      • Henshall C.
      • Mestre-Ferrandiz J.
      • et al.
      How long does biomedical research take? Studying the time taken between biomedical and health research and its translation into products, policy, and practice.
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      • Hu T.
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      • et al.
      Detecting change-point, trend, and seasonality in satellite time series data to track abrupt changes and nonlinear dynamics: A Bayesian ensemble algorithm.
      • Sangaralingham L.R.
      • Sangaralingham S.J.
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      • Yao X.
      • Dunlay S.M.
      Adoption of sacubitril/valsartan for the management of patients with heart failure.
      • Roth G.A.
      • Poole J.E.
      • Zaha R.
      • Zhou W.
      • Skinner J.
      • Morden N.E.
      Use of guideline-directed medications for heart failure before cardioverter-defibrillator implantation.
      ,
      • Singh S.M.
      • Austin P.C.
      • Chong A.
      • Alter D.A.
      Coronary angiography following acute myocardial infarction in Ontario, Canada.
      . The care gap observed during earlier periods and in younger individuals in this study has important consequences as it has been suggested that optimizing sacubitril/valsartan use in eligible HFrEF patients in Canada could reduce heart-failure hospitalizations and HF-associated deaths by 15%
      • Huitema A.A.
      • Daoust A.
      • Anderson K.
      • Poon S.
      • Virani S.
      • White M.
      • et al.
      Optimal usage of sacubitril/valsartan for the treatment of heart failure: The importance of optimizing heart failure care in Canada.
      leading to major cost savings for the health care system and increased longevity for patients.
      Multiple factors likely played a role in the delayed uptake of sacubitril/valsartan in this cohort. We suspect clinical factors were unlikely the dominant reasons for delayed drug use as the odds for receipt of sacubitril/valsartan was highest in patients with clinical HF. Underutilization due to lack of drug tolerability secondary to hypotension or renal dysfunction is less plausible as systolic blood pressure, potassium and creatinine clearance were similar in the group that did and did not receive sacuitril/valsartan. Furthermore, the increasing use of sacubitril/valsartan with time argues against low drug use due to lack of patient tolerability as it is not likely that there was a dramatic change in clinical characteristics favoring drug tolerability during the study period. Lack of expert opinion is also less likely as guideline recommendations were available prior to an observed increase in the rate of sacubitril/valsartan prescription. We were unable to account for the impact for the COVID-19 pandemic on physician practice and patient uptake of new drug therapies in this study and as such cannot eliminate the influence of the pandemic on the uptake of this drug.
      It is possible physicians may not consider it necessary to be on sacubitril/valsartan prior to ICD implantation as data on the efficacy of ICDs was available prior to the advent of this drug
      • Moss A.J.
      • Zareba W.
      • Hall W.J.
      • Klein H.
      • Wilber D.J.
      • Cannom D.S.
      • et al.
      Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
      • Kadish A.
      • Dyer A.
      • Daubert J.P.
      • Quigg R.
      • Estes N.A.M.
      • Anderson K.P.
      • et al.
      Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.
      It is also possible that treating physicians may estimate the benefits of ICDs and cardiac resynchronization therapy (CRT) outweigh those provided by sacubitril/valsartan (and given the low rate (44%) of MRA use in this cohort, possibly pharmacologic therapy in general) and as such defer initiating or optimizing this and other pharmacologic agents until after ICD insertion has taken place. Harmonization of ICD and HF guidelines may be necessary to optimize the use and timing of drug and device therapy in patients with HFrEF.
      The increased odds of drug prescription with time and differential rate of prescription of sacubitril/valsartan in individual’s ≥65 versus <65 years highlights the importance of drug coverage on drug utilization. As sacubitril/valsartan is equally efficacious in patients regardless of age
      • McMurray J.J.V.
      • Packer M.
      • Desai A.S.
      • Gong J.
      • Lefkowitz M.P.
      • Rizkala A.R.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      , it is quite possible that a lower rate of use in patients <65 years may prevent a large subset of high-risk individuals from profiting from the benefits associated with this drug. Ensuring equitable access to this essential medication, and others of its kind, in a younger population with severe HFrEF is important given the chronic nature of this disease and the fact that the benefits are seen regardless of the age of onset.
      Several limitations to our work merit consideration. First, as a single-centre study our data may reflect local physician practice which might limit generalizability to other settings. Our work still has merit given that the patient population was similar to those reported in heart failure trials, our physician referral base included a large number of physicians in different practice settings (office- and/or hospital-based general cardiology and heart failure specialists) and locales (urban and rural). Second, while we collected data on drug prescription, adherence including initiation and subsequent discontinuation prior to ICD insertion (for example due to transient hypotension), and initiation post ICD implantation, was not uniformly available. As well, patient preference for drug use was not captured in our analysis. Third, our sample size is relatively small and as such we may not have had sufficient power to identify all statistically significant predictors associated with the use of sacubitril/valsartan. Indeed, many of our statistically non-significant predictors barely crossed unity. Our approach however allowed collection of important granular clinical data (creatinine, electrolytes and blood pressure) which impact decisions to prescribe sacubitril/valsartan, as well as data on drug use in patients <65 years. While a prospective study may have permitted more complete data collection, the associated Hawthorne effect would impact prescribing practices and prevent insight into the “natural history” of physician prescribing patterns for sacubitril/valsartan in clinical practice.

      CONCLUSIONS:

      In this contemporary cohort of patients undergoing primary prevention ICD insertion, increasing use of sacubitril/valsartan was observed, notably in those ≥65 years and after the availability of drug coverage. Understanding specific barriers and promoting its use in this population is recommended to improve clinical outcomes and survival in this high-risk patient population.

      FUNDING:

      This work was funded by a donation to the Sunnybrook Foundation from the Horgan Family.

      DISCLOSURES:

      There are no relevant disclosures in association with this work.

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