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Intensity of Guideline-Directed Medical Therapy for Coronary Heart Disease and Ischemic Heart Failure Outcomes

Open AccessPublished:November 09, 2020DOI:https://doi.org/10.1016/j.amjmed.2020.10.017

      Abstract

      Purpose

      The impact of guideline-directed medical therapy for coronary heart disease in those hospitalized with acute heart failure is unknown.

      Methods

      We studied guideline-directed medical therapies for coronary disease: angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), beta-adrenoreceptor antagonists, antiplatelet agents or anticoagulants, and statins. Using inverse probability of treatment weighting the propensity score, we examined associations of guideline-directed medical therapy intensity (categorized as low [0-1], high [2-3], or very high [4] number of drugs) with mortality in 1873 patients with angina, troponin elevation, or prior myocardial infarction.

      Results

      At discharge, 0-1, 2-3, and 4 medications were prescribed in 467 (25%), 705 (38%), and 701 (37%) patients, respectively. Relative to those prescribed 0-1 drugs (reference), all-cause mortality was lower with 2-3 (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.28-0.84, P = 0.009) or all 4 drug classes (HR 0.56, 95% CI 0.33-0.96, P = 0.034) over 181-365 days, with similar reductions present from 0-180 days. In those with heart failure with preserved ejection fraction, mortality trended lower with 2-3 drug classes (HR 0.43, 95% CI 0.18-1.02, P = 0.054) and was significantly reduced with 4 drugs (HR 0.32, 95%CI 0.12-0.84, P = 0.021) during 0-180 day follow-up. In heart failure with reduced ejection fraction, all-cause mortality was reduced during both 0-180 and 181-365 days when discharged on 2-3 (HR 0.30 for 181-365 days, 95%CI 0.14-0.64, P = 0.002) or all 4 drug classes (HR 0.43, 95%CI 0.19-0.95, P = 0.038).

      Conclusions

      Increasing guideline-directed medical therapy intensity for coronary heart disease resulted in lower mortality in patients with acute ischemic heart failure with both preserved and reduced ejection fractions.

      Keywords

      Clinical Significance
      • In patients with hospitalized acute heart failure and concomitant evidence of coronary heart disease, we found that greater use of guideline-directed medical therapies for coronary disease was associated with lower mortality.
      • The use of all 4 anti-ischemic drugs classes, including angiotensin-converting enzyme [ACE] inhibitors or angiotensin II receptor blockers [ARBs], beta-blockers, antiplatelets or anticoagulants, and statins, was associated with reduced risk of death in those with heart failure with reduced and also preserved left ventricular ejection fraction.

      Introduction

      Heart failure is a leading cause of mortality with more than 300,000 deaths per year in North America alone.
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      In contrast, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), beta-adrenoreceptor antagonists, statins, and antiplatelets or anticoagulants have been shown to significantly reduce mortality in patients with coronary heart disease.
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      Task Force Members
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      It is unknown whether the intensity of guideline-recommended therapy for coronary heart disease is associated with improved survival in those with concomitant heart failure. The objective of this study was to examine whether an increasing number of pharmacotherapeutic agents prescribed for coronary heart disease (ie, guideline-directed medical treatment intensity) was associated with lower mortality risk. Because improved outcomes could occur by new drug initiation or continuation of preadmission medications, we hypothesized that greater provision of anti-ischemic guideline-directed medical treatments for coronary disease at discharge would be associated with reductions in mortality and cardiovascular hospitalization in patients with acute ischemic heart failure. If true, such findings could highlight the importance of not only optimizing heart failure therapies at discharge but also those of ischemic heart disease.

      Methods

      Study Population and Design

      The study design has been published.
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      • Wang X
      • Ge Y
      • et al.
      Comparison of troponin elevation, prior myocardial infarction, and chest pain in acute ischemic heart failure.
      Briefly, we studied patients ages ≥18 years admitted to hospital from 70 emergency departments in Ontario, Canada, between April 1, 2010, and March 31, 2013, with both the Framingham heart failure criteria at presentation and a final discharge diagnosis of heart failure (International Classification of Diseases code I50) in the Canadian Institute for Health Information discharge abstract.
      • Freitas C
      • Wang X
      • Ge Y
      • et al.
      Comparison of troponin elevation, prior myocardial infarction, and chest pain in acute ischemic heart failure.
      We excluded patients with: 1) low-acuity triage score on the emergency department Canadian Triage and Acuity Scale to ensure enrollment of acute patients, 2) heart failure occurring after hospital admission, 3) b-type natriuretic peptide or NT-proBNP that were not indicative of heart failure as per the Canadian Cardiovascular Society guidelines (ie, <100 pg/mL and <300 pg/mL, respectively) in the absence of Framingham criteria, 4) death in-hospital prior to discharge, 5) missing demographic data, and 6) palliative status.
      • Van Spall HG
      • Atzema C
      • Schull MJ
      • et al.
      Prediction of emergent heart failure death by semi-quantitative triage risk stratification.
      As described previously, we included those with coronary heart disease defined as any of the following: prior myocardial infarction, previous coronary revascularization, admission troponin elevated above the upper limit of normal, angiographic or computed tomographic evidence of >50% stenosis of an epicardial vessel, or noninvasive imaging highly suggestive of coronary artery disease (eg, fixed or reversible defects of medium or large size on single-photon emission computed tomography (SPECT) myocardial perfusion imaging, moderate or severe resting or ischemic wall motion abnormality on stress echocardiography, or moderate or large defects on myocardial viability testing). To ensure that the study cohort was eligible for all 4 drug classes, we excluded patients who: 1) had documented allergy, intolerance, or contraindications to any of the 4 pharmacotherapies,
      • McKelvie RS
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      • et al.
      Canadian Cardiovascular Society quality indicators for heart failure.
      ,
      • Tran CT
      • Lee DS
      • Flintoft VF
      • et al.
      CCORT/CCS quality indicators for acute myocardial infarction care.
      2) predischarge serum creatinine ≥2.5 mg/dL or serum potassium ≥5.5 mEq/L, 3) predischarge systolic blood pressure <90 mm Hg, 4) bilateral renal artery stenosis, 5) active pregnancy, 6) severe aortic stenosis, 7) symptomatic bradycardia, 8) second- or third-degree atrioventricular block, 9) severe asthma or chronic obstructive pulmonary disease, 10) platelet count <100 × 109/L, 11) acute clinically significant bleeding, and 12) severe liver disease or cirrhosis.

      Data Sources

      We identified patients presenting to the emergency department using the National Ambulatory Care Reporting System and hospitalizations using the Canadian Institute for Health Information Discharge Abstract Database. Both databases use the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10-CA). The stratified cluster sampling strategy for patient selection has been described previously (see Supplementary Text, available online).
      • Freitas C
      • Wang X
      • Ge Y
      • et al.
      Comparison of troponin elevation, prior myocardial infarction, and chest pain in acute ischemic heart failure.
      Data were collected by highly trained, specialized nurse or physician abstractors from hospital medical records using electronic case report forms with automated range checks, double-data entry for key variables, and preloaded medical record numbers. Information was retrieved on demographics, clinical characteristics (including cardiac and noncardiac conditions), medications, laboratory tests, and left ventricular function evaluation. Cardiovascular hospitalizations were determined using ICD-10-CA codes in the Canadian Institute for Health Information Discharge Abstract Database (see Supplementary Table 1, available online). The Registered Persons Database was used to identify deaths, and the Ontario Registrar General Database was used to identify causes of death. The ICES Mother-Baby Database (MOMBABY) provided birth records to identify pregnant patients, who were deemed ineligible for ACE inhibitors or ARBs.

      Outcome Measures

      The 2 coprimary outcomes were all-cause mortality and cardiovascular death after index heart failure hospital discharge up to 1-year follow-up. Secondary outcomes included cardiovascular hospitalizations and the composite of cardiovascular hospitalizations or death within 1 year after the index hospital discharge. In the event of a violation of the proportional hazards assumption, we planned to divide the follow-up period into 0-180 and 181-365 day time frames.

      Statistical Analysis

      Baseline characteristics by treatment intensity were compared for those prescribed 0-1, 2-3, or 4 drug classes at hospital discharge and presented using medians (interquartile range) or proportions. We conducted 2 comparisons comparing different treatment intensities: 1) pairwise comparison of 2-3 versus 0-1 drugs and 2) pairwise comparison of 4 versus 0-1 drugs. We accounted for baseline differences between the treatment intensity groups using inverse probability of treatment weighting the propensity score. Weighted standardized differences were calculated to assess the covariate balance between groups.
      • Austin PC
      • Stuart EA
      Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies.
      The hazard of the outcome was compared between groups using either a weighted Cox proportional hazards model (for outcomes that included all-cause mortality) or a weighted cause-specific hazard model (for outcomes for which noncardiovascular death was a competing risk), with a robust, sandwich variance estimator.
      • Austin PC
      The performance of different propensity score methods for estimating marginal hazard ratios.
      In inverse probability of treatment weighting using the propensity score, we weighted for variables in the validated Enhanced Feedback For Effective Cardiac Treatment (EFFECT) and Emergency Heart failure Mortality Risk Grade (EHMRG30-ST) models.
      • Lee DS
      • Austin PC
      • Rouleau JL
      • Liu PP
      • Naimark D
      • Tu JV
      Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model.
      ,
      • Lee DS
      • Lee JS
      • Schull MJ
      • et al.
      prospective validation of the emergency heart failure mortality risk grade for acute heart failure.
      These included age, transport by emergency medical services, systolic blood pressure, heart rate, respiratory rate, oxygen saturation, presence of comorbid cerebrovascular disease, chronic pulmonary disease, dementia, active cancer, presenting hemoglobin, sodium concentration, potassium concentration, creatinine concentration, presence of troponin elevation, prior metolazone use, and ST depression on 12-lead electrocardiogram. We also weighted for the following variables: sex, prior myocardial infarction, diabetes, hypertension, peripheral artery disease, atrial fibrillation or flutter, left ventricular function (ie, heart failure with reduced [<40%], mid-range [40%-49%], preserved [≥50%], or unknown ejection fraction), prior percutaneous coronary intervention or coronary artery bypass graft surgery, and hospital volume (≤350 vs >350 annual visits to the emergency department for heart failure) in the propensity score model. We also tested for an interaction between number of guideline-directed medical treatment classes and left ventricular ejection fraction category.
      Weighted cumulative incidence functions were constructed to compare primary and secondary outcomes. The proportional hazards assumption was tested. All analyses were performed with SAS software (SAS Institute, version 9.4, Cary, NC). Research ethics approval was obtained from all hospitals prior to data abstraction.

      Results

      Cohort Characteristics

      Among 3723 patients with acute heart failure and coronary heart disease, 1873 remained after exclusions (Figure 1), comprised of 467 (25%) patients prescribed 0-1 drug, 705 (38%) prescribed 2-3 drugs, and 701 (37%) prescribed all 4 anti-ischemic medications. Those in the 2- to 3-drug group exhibited high rates of use of antiplatelets or anticoagulants (83.3%), beta-blockers (70.8%), and modest rates of ACE inhibitors or ARBs (61.0%) as shown in Table 1. There was no difference in preadmission use of other heart failure medications (Supplementary Table 2, available online). Increasing number of drug classes at discharge was associated with heart failure with reduced ejection fraction, lower creatinine, and younger age (Table 1).
      Table 1Baseline Characteristics
      Median (IQR) or n (%)0-1 drugs2-3 drugs4 drugs
      N467705701
      Demographic
       Age, years77 (67, 84)76 (66, 83)74 (65, 81)
       Men294 (63.0%)411 (58.3%)449 (64.1%)
      Presenting features
       Transport by EMS201 (43.0%)355 (50.4%)311 (44.4%)
       Angina123 (26.3%)320 (45.4%)325 (46.4%)
       Systolic BP, mm Hg141 (121, 162)145 (125, 165)143 (126, 164)
       Heart rate, beats/min87 (72, 106)91 (76, 112)89 (74, 110)
       Oxygen saturation, %96 (93, 98)96 (93, 98)96 (92, 98)
      Comorbid conditions
       Diabetes198 (42.4%)297 (42.1%)352 (50.2%)
       Hypertension335 (71.7%)520 (73.8%)589 (84.0%)
       Cerebrovascular disease77 (16.5%)120 (17.0%)105 (15.0%)
       Peripheral artery disease57 (12.2%)67 (9.5%)80 (11.4%)
       Chronic pulmonary disease50 (10.7%)84 (11.9%)62 (8.8%)
       Dementia27 (5.8%)35 (5.0%)21 (3.0%)
       Active cancer65 (13.9%)109 (15.5%)90 (12.8%)
       Prior MI225 (48.2%)295 (41.8%)371 (52.9%)
       Prior PCI procedure90 (19.3%)127 (18.0%)166 (23.7%)
       Prior CABG surgery129 (27.6%)149 (21.1%)182 (26.0%)
      Laboratory features
       Hemoglobin, g/L124 (110, 139)124 (109, 141)128 (113, 143)
       White blood count, x 109 cells/L8.9 (6.9, 11.6)9.1 (7.1, 11.4)8.9 (7.2, 11.5)
       Sodium, mmol/L139 (136, 141)138 (136, 141)138 (136, 140)
       Potassium, mmol/L4.1 (3.8, 4.4)4.1 (3.7, 4.4)4.0 (3.7, 4.3)
       Creatinine, umol/L106 (84, 132)106 (84, 138)99 (79, 121)
       Troponin > ULN208 (44.5%)493 (69.9%)433 (61.8%)
      ECG features
       Atrial fibrillation or flutter138 (29.6%)178 (25.2%)184 (26.2%)
       QRS duration, msec108 (90, 140)106 (91, 140)106 (92, 140)
      Echocardiography
       HFrEF204 (43.7%)427 (60.6%)443 (63.2%)
       HFmEF27 (5.8%)38 (5.4%)49 (7.0%)
       HFpEF68 (14.6%)112 (15.9%)98 (14.0%)
       LVEF unknown168 (36.0%)128 (18.2%)111 (15.8%)
      Preadmission medications
       Antiplatelet or anticoagulant165 (35.3%)290 (41.1%)305 (43.5%)
       Beta-blocker234 (50.1%)340 (48.2%)470 (67.0%)
       ACE inhibitor or ARB213 (45.6%)364 (51.6%)517 (73.8%)
       Statin221 (47.3%)374 (53.0%)516 (73.6%)
       Digoxin45 (9.6%)74 (10.5%)56 (8.0%)
       Furosemide230 (49.3%)310 (44.0%)293 (41.8%)
       Spironolactone/eplerenone34 (7.3%)43 (6.1%)39 (5.6%)
      Discharge medications
       Antiplatelet or anticoagulant33 (7.1%)587 (83.3%)701 (100.0%)
       Beta-blocker24 (5.1%)499 (70.8%)701 (100.0%)
       ACE inhibitor or ARB9 (1.9%)430 (61.0%)701 (100.0%)
       Statin7 (1.5%)407 (57.7%)701 (100.0%)
      ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BP = blood pressure; CABG = coronary artery bypass graft; ECG = electrocardiogram; EMS = emergency medical services; HFmEF = heart failure with middle-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; IQR = interquartile range; LVEF = left ventricular ejection fraction; MI = myocardial infarction; PCI = percutaneous coronary intervention; ULN = upper limit of normal.

      Unadjusted Outcomes

      A total of 1646 person-years of follow-up were examined. The cumulative 1-year incidence of cardiovascular death was 0.165, 0.108, and 0.103, with 77, 76, and 72 cardiovascular deaths in those prescribed 0-1, 2-3, and 4 drugs, respectively. The cumulative 1-year incidence of total mortality was 0.270, 0.183, and 0.160 with 126, 129, and 112 deaths, in those prescribed 0-1, 2-3, and 4 drugs, respectively. The cumulative 1-year incidence of cardiovascular hospitalization was 0.473, 0.441, and 0.431, corresponding to 221, 311, and 302 events, in those with 0-1, 2-3, and 4 drugs, respectively. There were 275, 359, and 327 composite 1-year events (total death or cardiovascular hospitalization) in those taking 0-1, 2-3, and 4 drugs. The cumulative incidence of composite outcomes was 0.589 0.509, and 0.466 in those with 0-1, 2-3, and 4 drugs, respectively.

      Comparison of Treatment Groups After Propensity-Score Weighting

      Supplementary Figures 1 and 2, available online, show standardized differences before and after propensity score weighting. All standardized differences after propensity weighting were <0.10, indicating that acceptable balance had been achieved. Cumulative incidence curves for all-cause mortality after propensity weighting demonstrated lower incidence of death in those with higher drug intensity (Figure 2). Propensity-weighted cumulative incidence curves demonstrated lower incidence of cardiovascular hospitalization or total mortality with 2-3 or 4 guideline-directed medical treatments compared with 0-1 drugs (Figure 3). A similar pattern was observed for cardiovascular death (Supplementary Figure 3, available online).
      Figure 2
      Figure 2Cumulative incidence of all-cause mortality after propensity weighting in those discharged on 2-3 (left panel) or 4 (right panel) compared with 0-1 guideline-directed medical therapies.
      Figure 3
      Figure 3Cumulative incidence of death or cardiovascular hospitalization after propensity weighting in those discharged on 2-3 (left panel) or 4 (right panel) compared with 0-1 guideline-directed medical therapies.
      Supplementary Figure 1
      Supplementary Figure 1Standardized differences in 2-3 versus 0-1 drug class groups before and after propensity score weighting. BP = blood pressure; CABG = coronary artery bypass graft; COPD = chronic obstructive pulmonary disease; EMS = emergency medical services; HFmEF = heart failure with middle-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; HF, ED = heart failure, emergency department; LVEF = left ventricular ejection fraction; MI = myocardial infarction; PCI = percutaneous coronary intervention; PS = propensity scrore; ULN = upper limit of normal.
      Supplementary Figure 2
      Supplementary Figure 2Standardized differences in 4 versus 0-1 drug class groups before and after propensity score weighting. BP = blood pressure; CABG = coronary artery bypass graft; COPD = chronic obstructive pulmonary disease; EMS = emergency medical services; HFmEF = heart failure with middle-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; HF, ED = heart failure, emergency department; LVEF = left ventricular ejection fraction; MI = myocardial infarction; PCI = percutaneous coronary intervention; ULN = upper limit of normal.
      Supplementary Figure 3
      Supplementary Figure 3Cumulative incidence of cardiovascular death after propensity weighting in those discharged on 2-3 (left panel) or 4 (right panel) compared to 0-1 guideline-directed medical therapies.
      After inverse probability of treatment weighting, there was a violation of the proportional hazards assumption. Therefore, follow-up was divided into 2 periods: 0-180 and 181-365 days, which satisfied the proportional hazards assumption. After propensity-weighting, from 0-180 days, all-cause mortality was significantly reduced in those prescribed 2-3 drugs (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.40-0.80, P = 0.001) and even further reduced in those prescribed 4 drugs (HR 0.47, 95% CI 0.31-0.71, P < 0.001) (Table 2). From 181-365 days, all-cause mortality continued to be significantly reduced with 2-3 and 4 drugs (Table 2). Similarly, cardiovascular death was significantly reduced at both time points (Table 2). There were significant reductions in the composite outcome of death or cardiovascular hospitalization at both 0-180 and 181-365 time points when 4 guideline-directed medical treatments were employed (Table 2).
      Table 2Effect of Number of Medications on Mortality, Hospitalization, or Composite Events After Propensity Weighting in the Entire Cohort
      OutcomeTime PeriodNo. of DrugsHazard Ratio (95% CI)P Value
      CV mortality0-180 days0-11.0 (Referent)
      2-30.66 (0.43, 1.01)0.056
      40.47 (0.27, 0.82)0.008
      181-365 days0-11.0 (Referent)
      2-30.34 (0.16, 0.72)0.005
      40.49 (0.25, 0.95)0.035
      Total death0-180 days0-11.0 (Referent)
      2-30.56 (0.40, 0.80)0.001
      40.47 (0.31, 0.71)<0.001
      181-365 days0-11.0 (Referent)
      2-30.48 (0.28, 0.84)0.009
      40.56 (0.33, 0.96)0.034
      CV hospitalization0-180 days0-11.0 (Referent)
      2-30.84 (0.67, 1.05)0.126
      40.86 (0.68, 1.10)0.229
      181-365 days0-11.0 (Referent)
      2-31.12 (0.73, 1.71)0.611
      40.68 (0.43, 1.09)0.109
      Total death or CV hospitalization0-180 days0-11.0 (Referent)
      2-30.73 (0.60, 0.89)0.002
      40.68 (0.55, 0.85)<0.001
      181-365 days0-11.0 (Referent)
      2-30.96 (0.65, 1.44)0.856
      40.65 (0.42, 0.99)0.045
      CI = confidence interval; CV = cardiovascular.

      Mortality Outcomes Stratified by Ejection Fraction

      When the inverse probability of treatment weighting analysis was stratified by left ventricular ejection fraction (reduced [n = 1074], mid-range [n = 114], or preserved [n = 278]), significant reductions in all-cause mortality were observed for 2-3 and 4 therapeutic classes compared with 0-1 drugs, particularly in those with reduced ejection fraction (Table 3). Total mortality was reduced in those with heart failure with preserved ejection fraction if all 4 drugs were used up to 180 days (Table 3). There were too few deaths (<10 in each group) to precisely estimate the effect of drug intensity in those with mid-range ejection fraction.
      Table 3Total Mortality Stratified by Left Ventricular Ejection Fraction Category in Propensity-Weighted Analysis
      SubgroupTime PeriodNo. of DrugsHazard Ratio (95%CI)P Value
      HFrEF0-180 days0-11.0 (Referent)
      2-30.54 (0.34, 0.88)0.014
      40.48 (0.28, 0.83)0.008
      181-365 days0-11.0 (Referent)
      2-30.30 (0.14, 0.64)0.002
      40.43 (0.19, 0.95)0.038
      HFmEF0-180 days0-11.0 (Referent)
      2-30.37 (0.07, 1.88)0.232
      41.02 (0.25, 4.18)0.978
      181-365 days0-11.0 (Referent)
      2-31.16 (0.24, 5.53)0.855
      41.08 (0.21, 5.57)0.923
      HFpEF0-180 days0-11.0 (Referent)
      2-30.43 (0.18, 1.02)0.054
      40.32 (0.12, 0.84)0.021
      181-365 days0-11.0 (Referent)
      2-30.49 (0.13, 1.80)0.284
      40.57 (0.17, 1.87)0.355
      CI = confidence interval; HFmEF = heart failure with middle-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction.
      Supplementary Table 1Cardiovascular Disease Diagnosis Codes
      DiagnosisInternational Classification of Diseases, Tenth Revision (ICD-10) codes
      Heart failureI50
      Ischemic heart diseaseI20-I25
      Other cardiovascular disease codes
       ArrhythmiaI44-I49
       Atrial fibrillationI48
       Ventricular arrhythmiaI49.0, I47.2
       Myo-/peri-/endocardial diseaseI30-I33, I40-I43, I51.4
       Cerebrovascular diseaseI60-I69
       Hypertensive diseaseI10-I13, I15
       Pulmonary vascular diseaseI26-I28
       Peripheral vascular diseaseI70-I74, I77-I82, R02
       Rheumatic heart diseaseI00-I02, I05-I09
       ShockR57
       Syncope, Sudden deathR55, R96.0
       Valvular heart diseaseI34-I39
       Other cardiacI51, I52, I95, I97
      Supplementary Table 2Other Preadmission Medications, n (%)
      Preadmission medications0-1 drugs2-3 drugs4 drugsP value
       Digoxin45 (9.6%)74 (10.5%)56 (8.0%)0.263
       Furosemide209 (44.8%)309 (43.8%)293 (41.8%)0.569
       Metolazone8 (1.7%)14 (2.0%)SC0.06
       Aldosterone antagonist34 (7.3%)43 (6.1%)39 (5.6%)0.487
      SC = small cells.

      Discussion

      The coexistence of coronary heart disease and heart failure is commonly encountered in practice, but gaps exist in the optimal treatment of multiple conditions that disease-specific guidelines do not address. We found that greater intensity of guideline-directed medical treatments for coronary heart disease (ACE inhibitors or ARBs, beta-blockers, statins, antiplatelet agents or anticoagulants) at hospital discharge was associated with reduced risk of all-cause and cardiovascular mortality in patients hospitalized with acute ischemic heart failure. There were similar beneficial trends or significant reductions in the composite of death or cardiovascular hospitalization. Additionally, total mortality was significantly reduced when 4 guideline-directed medical treatments were used in heart failure with preserved ejection fraction and was reduced in all time periods in those with reduced ejection fraction.
      There is a paucity of evidence regarding optimization of medical therapy in patients with acute decompensated heart failure resulting from an ischemic etiology. Several studies have indicated that evidence-based therapies are not implemented optimally in patients with heart failure overall.
      • Allen LA
      • Fonarow GC
      • Liang L
      • et al.
      Medication initiation burden required to comply with heart failure guideline recommendations and hospital quality measures.
      • Teng TK
      • Tromp J
      • Tay WT
      • et al.
      Prescribing patterns of evidence-based heart failure pharmacotherapy and outcomes in the ASIAN-HF registry: a cohort study.
      • Lee DS
      • Tu JV
      • Juurlink DN
      • et al.
      Risk-treatment mismatch in the pharmacotherapy of heart failure.
      We examined those with ischemic heart failure, a high-risk group who have an increased rate of mortality and hospitalizations.
      • Chun S
      • Tu JV
      • Wijeysundera HC
      • et al.
      Lifetime analysis of hospitalizations and survival of patients newly admitted with heart failure.
      ,
      • Lee DS
      • Lee JS
      • Schull MJ
      • et al.
      prospective validation of the emergency heart failure mortality risk grade for acute heart failure.
      ,
      • Badar AA
      • Perez-Moreno AC
      • Jhund PS
      • et al.
      Relationship between angina pectoris and outcomes in patients with heart failure and reduced ejection fraction: an analysis of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA).
      Despite narrowing the cohort to those without any contraindications to all 4 drugs, 63% were not prescribed optimal medical therapy, and 25% were treated with only 1 or no guideline-directed medical treatments for coronary heart disease. Similar to our study, the rates of 1-year use of coronary heart disease therapies in patients postrevascularization for acute coronary syndrome or stable coronary disease was low.
      • Pinho-Gomes AC
      • Azevedo L
      • Ahn JM
      • et al.
      Compliance with guideline-directed medical therapy in contemporary coronary revascularization trials.
      This highlights the challenges of implementing and maintaining guideline-directed medical treatments across multiple areas of cardiovascular medicine.
      In our analysis of guideline-directed medical therapies, we included antiplatelet agents and HMG-coA reductase inhibitors, which had neutral effects in randomized trials. The Effect of Rosuvastatin in Patients With Chronic Heart Failure (GISSI-HF) and Controlled Rosuvastatin Multinational Trial Trial in Heart Failure (CORONA) trials did not demonstrate a beneficial effect of statins in those with heart failure with reduced ejection fraction, possibly because of the inclusion of patients with nonischemic and varying spectrum of ischemic etiologies.
      • Kjekshus J
      • Apetrei E
      • Barrios V
      • et al.
      Rosuvastatin in older patients with systolic heart failure.
      ,
      • Tavazzi L
      • Maggioni AP
      • Marchioli R
      • et al.
      Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
      In A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure (COMMANDER HF), low-dose rivaroxaban did not impact mortality, stroke, or myocardial infarction in those with heart failure with reduced ejection fraction and coronary artery disease.
      • Zannad F
      • Anker SD
      • Byra WM
      • et al.
      Rivaroxaban in patients with heart failure, sinus rhythm, and coronary disease.
      However, patients with prior heart failure enrolled in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome - Thrombolysis in Myocardial Infarction 51 trial (ATLAS ACS 2-TIMI 51), who were treated with rivaroxaban in addition to dual-antiplatelet therapy experienced a reduction in cardiovascular death, myocardial infarction, or stroke.
      Janssen Research and Development
      Advisory committee briefing document: ATLAS ACS 2 TIMI 51.
      Guideline-directed medical therapies may also vary in their effectiveness depending on the context and severity of the patient. For example, the benefits of beta-blockers in coronary heart disease may be time dependent, with greater benefits after recent acute ischemic events.
      • Bangalore S
      • Steg G
      • Deedwania P
      • et al.
      Beta-blocker use and clinical outcomes in stable outpatients with and without coronary artery disease.
      The mechanism for the benefits of guideline-directed medical therapies was not due to inability to safely take these medications because of potential contraindications. The benefits were also not driven solely by ACE inhibitors or ARBs and beta-blockers, which have been shown to improve survival in heart failure with reduced ejection fraction because patients prescribed all 4 drugs tended to have better and more consistently improved outcomes. Patients who present with decompensated heart failure and concomitant evidence of an ischemic etiology are at high risk for adverse outcomes. For example, patients with heart failure and prior myocardial infarction or even mild elevation of troponin at presentation have the poorest outcomes.
      • Braga JR
      • Tu JV
      • Austin PC
      • et al.
      Outcomes and care of patients with acute heart failure syndromes and cardiac troponin elevation.
      ,
      • Lee DS
      • Gona P
      • Vasan RS
      • et al.
      Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the Framingham Heart Study of the national heart, lung, and blood institute.
      Provision of guideline-directed medical therapies for the underlying pathophysiological condition may allow for quiescence of adverse consequences relating to coronary heart disease, thus, benefitting such patients in the near term.
      Traditionally, the management of heart failure emphasizes treatment based on left ventricular ejection fraction and underemphasizes the underlying cause of the heart failure. There are also few ways to impact survival in patients with acute decompensated heart failure in general and, the subgroup of preserved ejection fraction, specifically. Consequently, the management plan in heart failure with preserved ejection fraction is typically focused on symptom reduction; however, our findings suggest that survival in these patients may be improved by optimization of therapies in those with concomitant coronary heart disease.
      • Ezekowitz JA
      • O'Meara E
      • McDonald MA
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure.
      Optimizing targeted therapy for coronary disease is a widely applicable and noninvasive approach to narrowing treatment gaps in the care of heart failure.
      Our study has several important limitations. Although we used propensity weighting to balance key baseline characteristics between comparison groups, unmeasured confounding may persist. Among our cohort, 25% were prescribed 0-1 drugs at discharge, and while the reasons for this were beyond the scope of our study, both patient and physician factors may have contributed. For example, the patient's goals of care may have changed at discharge, or a physician may have perceived the patient to be too high or low risk to institute therapy. However, altered goals of care should not lead to drug discontinuation, which could reduce morbidity and improve quality of life. We were also unable to assess whether patients attained target doses of guideline-directed medical therapies. Beta-blockers might not be tolerated in patients with chronic obstructive lung disease or asthma, and consequently, we excluded such patients from the analysis. We only examined medications prescribed at discharge, and we were unable to limit the study to naïve users because too few patients were on none of these drugs at the time of hospital presentation. Some medications were not available during the time period of the study, such as sodium-glucose linked cotransporter inhibitors, and could not be evaluated. However, this presents an advantage because it allows for a separate evaluation of the impacts of guideline-directed medical therapies for coronary heart disease without cointervention from these agents. Finally, the number of patients in the middle-range ejection fraction stratum was small; therefore, we were unable to precisely estimate benefits in this subgroup.

      Conclusions

      In conclusion, patients with ischemic heart failure who were discharged on a greater number of guideline-directed medical therapies for coronary heart disease, including ACE inhibitors or ARBs, beta-blockers, anticoagulants or antiplatelet agents, and statins, demonstrated improved survival, reduced cardiovascular mortality and reduction in the composite of death or cardiovascular readmission events. Although the results were consistent across left ventricular function categories, total mortality was predominantly reduced in those with reduced ejection fraction and those with preserved ejection fraction when prescribed all 4 medications. Greater use of guideline-directed medical therapies for coronary heart disease in those with acute heart failure may represent an immediate and broadly applicable approach to improve patient outcomes.

      Supplementary Text

      We used stratified cluster sampling to select patients admitted to hospitals in Ontario that had an emergency department on site and a yearly volume of greater than 50 patients with acute heart failure per year. Patients who presented to teaching, medium-sized (51-150 annual visits to emergency department for heart failure) and large (>150 annual visits to emergency department for heart failure) community hospitals, from April 1, 2010, to March 31, 2013, were eligible. If a patient had multiple visits during this period, only the first visit was included. Highly trained, specialized nurse or physician abstractors collected data on approximately 140 patients from each of 13 teaching and 30 large hospitals and approximately 50 patients from each of 27 medium-sized hospitals.

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