Abstract
Background:
Despite robust evidence and strong recommendations supporting the incremental and dose-related benefit of combined neurohormonal blockers (guideline‐directed medical therapy [GDMT]) in heart failure with reduced ejection fraction (HFrEF), real-world data shows significant gaps in uses and/or dosing of these therapies.
Rationale:
As heart failure (HF) hospitalization is viewed as an opportunity for the initiation and optimization of HF life-saving medications and the paucity of data exploring this important issue in Yemen, the current study aims to fill this gap.
Objective:
The objective of this study was to evaluate the use, number, and dose optimization of the GDMT in a cohort of hospitalized patients with HFrEF in Yemen.
Materials and Methods:
We included 1408 Yemeni patients with available ejection fraction (EF) enrolled in the Gulf CARE registry from February to November 2012. In this analysis, we included only four classes of GDMT, renin-angiotensin system inhibitors (RASi), evidence-based beta-blockers, and mineralocorticoid receptor antagonist (MRA). Each drug dose was converted to the equivalent daily dose of a selected representative drug. We explored the prescription of these drugs either separately or in combination and the target dose (TD) achievement for each drug at admission and discharge.
Results:
Among the1408 patients recruited, 916 patients (65%) were males and mean age was 53.5 ± 15.4 years, 53% (n = 748) presented with HFrEF (EF < 40%), 21% (n = 299) with HFpEF (EF ≥ 50%), and 26% (n = 361) with HFmrEF (Heart failure with mildly reduced ejection fraction) (EF 40-49%). Beta-blockers, renin-angiotensin system inhibitors, and MRA were prescribed to 28% (n = 400), 51% (n = 716), and 10% (n = 143) at baseline and 69.5% (n = 978), 82% (n = 1157), and 59% (n = 831) on discharge, respectively. The rate of TD achievement was (0.0% vs. 3.6% (n = 35]) for beta-blockers and (0.279% [n = 2] vs. 1.5% [n = 17]) for renin-angiotensin system inhibitors on baseline and discharge, respectively. Among 748 patients with HFrEF, 36% (n = 270) were not receiving any GDMT at baseline, while triple therapy was prescribed to 10% (n = 74) at baseline and 61.5% (n = 460) on discharge.
Conclusions:
A substantial gap in GDMT implementations with both underutilization and low TD achievement in patients with HFrEF in Yemen.
Keywords: Guideline‐directed medical therapy, heart failure, Yemen
INTRODUCTION
Background
The last three decades had witnessed a significant and major breakthrough in the medical treatment of heart failure with reduced ejection fraction (HFrEF) with the introduction of multiple disease-modifying therapies that altered the natural course of the disease with a proven benefit on morbidity, quality of life, and mortality.[1,2] Clinical trials established the neurohormonal blockade termed by international guidelines as “guideline-directed medical therapy (GDMT), as the cornerstone HFrEF therapy.[3,4,5] An incremental benefit of combined neurohormonal blockade was also demonstrated, where dual is better than single and triple is more beneficial than dual therapy.[6,7] On the basis of landmark randomized clinical trials, current guidelines recommend that unless contraindicated all patients with HFrEF should be treated with the GDMT, which includes evidence-based beta-blockers, renin-angiotensin-aldosterone system (RAAS) inhibitors, angiotensin-converting enzyme inhibitors (ACEIs) or if not tolerated, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs). Furthermore, for the best outcomes, these guidelines recommend an optimization of the GDMT at either the target (doses specified in clinical trials) or the highest tolerated dose.[3,4,5,8] Therefore, as per the guidelines, GDMT should be optimized, i. e., initiated and titrated to maximally tolerated recommended doses and clinicians should make every possible effort to achieve target doses (TDs) of GDMT to get the maximal benefits of GDMT.[3,4,5,8]
Rationale and aim of the study
Despite rigorous data supporting the benefits of GDMT and the strong professional recommendations by the heart failure (HF) guidelines,[3,4,5] and expert consensus decision pathway document,[8] their implementation and dose optimization among eligible patients with HFrEF remain suboptimal, which explain the lack of the established efficacy of GDMT seen in clinical trials, in real-world settings.[9,10,11,12,13,14,15]
Hospitalization for HF – whether attributable to new-onset (de novo) or worsening of established HF (HF decompensation), remains frequent,[9] costly, and also conveys a high risk of subsequent rehospitalization and mortality, especially the 1st months after discharge commonly defined as the “vulnerable period” or “vulnerable phase.”[16,17,18,19] Multiple evidences support the safety and beneficial effects of early in-hospital GDMT initiation and continuation of HF medications during an episode of AHF (Acute heart failure).[20,21,22,23,24] Moreover, consequently, hospitalization represents a window of opportunity for the initiation and optimization of HF life-saving medications. Despite that unfortunately, many data suggest a high rate of inhospital discontinuation, suboptimal titration as well as missed introduction and are associated with a worse prognosis.[13,25,26,27,28,29] Early inhospital prescription of GDMT increases the likelihood of chronic adherence, whereas deferring GDMT initiation to the outpatient setting carries a >75% chance therapies will never be started within the next year and has excess absolute mortality of ~1% per month that therapy is delayed.[29,30] Thus, uptitration to target dosages of GDMT should be started during hospital admission.[31,32,33,34] Based on the abovementioned importance of inhospital initiation and optimization of GDMT and the paucity of data exploring this important issue in Yemen, the current study aims to fill the gap. Besides that Yemen as one of the poorest countries in the world, faces unique challenges such as poor health care system, with limited resources, lack of HF specialists, and structured HF programs with specialized clinics. Obstacles on Yemeni patient’s side are important as, lack of awareness of HF treatment guidelines, training deficits, lack of health insurance, economic status, patients’ illiteracy, and self-care deficits. Worldwide physician-related factors contribute the most to clinical inertia. Unique obstacles on Yemeni healthcare providers are important as clinical inertia, lack of awareness and knowledge of HF treatment guidelines, and lack of education or training programs of healthcare providers. Limited availability and accessibility to the guidelines because of economic constraints are other well-identified contributors to clinical inertia in our country.
Objectives
The main purpose of this study was to evaluate the Yemeni physicians’ adherence to the evidence-based GDMT (renin-angiotensin system inhibitor [RASi], beta-blockers [BBs], and Mineralocorticoid receptor antagonists (MRA)) for patients with HFrEF in accordance with the current HF guidelines, using a real-life data which would reflect the current (actual) clinical practice. To verify such aim, the following more specific objectives were analyzed (at both time of admission and at discharge); (i) Proportions of patients who received GDMT separately and in combination and (ii) TDs achievement of GDMT in HFrEF (<40%) patients as per the European, and American HF guidelines. Our secondary objectives were (i) to study the characteristics of the drugs used in HF therapy in our country and (ii) to analyze the drug prescription across the different HF phenotypes.
MATERIALS AND METHODS
Data source
The Gulf aCute heArt failuRe rEgistry (Gulf CARE) is the first HF registry in the Gulf area. Its design and methodology have been previously described in detail.[35,36] In brief, it is a prospective, multinational, observational survey of patients admitted with AHF to 47 hospitals in seven Middle Eastern Gulf countries including Yemen, between February and November 2012.[35,36] Eligible patients were followed up at 3 months and at 1 year postdischarge. Data collected at the point of initial care and during hospitalization included: demographics, etiology, precipitating factors, comorbidities, clinical presentation, laboratory and imaging data, medications, and inhospital outcome. In addition, mortality data at 3-month and 12-month follow-up were collected. Data entry was done online using a custom-designed electronic case record form at the Gulf CARE website (www.gulfcare.org). Institutional or national ethical committee or review board approval was obtained in each of the seven participating countries. The study also conforms with the principles outlined in the Declaration of Helsinki. The study was also registered at clinicaltrials.gov (NCT01467973).
Inclusion criteria/exclusion criteria
Males and females 18 years of age or older, admitted to any of the participating hospitals with acute HF, were included in the registry. Acute HF was defined according to the HF guidelines.[37,38]
Current study population data analysis and patient categorization
Out of 5005 patients with AHF in the Gulf CARE, a total of 1536 Yemeni patients from eight major hospitals. For the purposes of the present analysis, we included 1408 patients (91.7%), patients with available left ventricular ejection fraction (LVEF data, leaving 128 patients (8.3%) with no such data. As most studies specifically looking at HFmrEF used the 2016 European guidelines[3] definition of HFmrEF as LVEF from 40% to 49%, we adopted such definition in this paper, therefore, we stratified our patients into three ejection fraction (EF) groups: reduced EF (HFrEF, have an EF <40%), midrange EF (HFmrEF, LVEF 40%–49%), and preserved EF (HFpEF, LVEF ≥50%).
Study variables and definitions
As per the objectives, drug therapy at the baseline (on admission) and at hospital discharge were analyzed. Medications were classified into two main groups; the first group included conventional HF medications as digoxin, diuretics, and anticoagulants. Only the rate of their prescription, at baseline, and on discharge was studied. Second group: guideline-directed medical therapies (GDMT) with proven mortality benefits. Although angiotensin receptor-neprilysin inhibitors (ARNis) and sodium–glucose cotransporter-2 (SGLT-2) inhibitors are currently included in GDMT and strongly recommended,[4,5,39] they have not been assessed in the current study as they were not available at time of study enrolment. Moreover, ivabradine and hydralazine, isosorbide dinitrate, due to low prescription rates, were not included. In this analysis, we included only four classes of GDMT, RASi, BBs, and MRA. The RASi include ACEIs and ARBs, the most commonly used agents were considered for analysis (i.e., captopril, lisinopril, enalapril, ramipril, valsartan, candesartan, and losartan), whereas perindopril and telmisartan excluded as they were infrequently prescribed. Spironolactone is the only available MRA. Only evidence-based BBs (i.e., bisoprolol, carvedilol, metoprolol succinate, and nebivolol) were considered for prescription and dose achievement rates.
Medication characteristics and outcome measures
As per the objectives, detailed analysis of the GDMT (the main outcome measures), regarding their prescription (proportions of patients prescribed GDMT, as separate drugs and in combination), types of drugs used, and dose optimization (rate of TD achievement for each drug, compared to the recommended regimen) both at time of admission and discharge among those with reduced EF (<40%) as recommended by the international HF guidelines, were done. To set out these measures, the following definitions were used; [Supplementary Tables 1 and 2].
Supplemental Table S1.
Evidence-based target doses of the Guideline-Directed Medical Therapy (GDMT), based on the ACC/AHA and ESC heart failure Guidelines
| Starting Dose (mg) | Target Dose (mg) | |
|---|---|---|
| ACE inhibitor | ||
| Captopril | 6.25 t.i.d. | 50 t.i.d. |
| Enalapril | 2.5 b.i.d. | 10–20 b.i.d. |
| Lisinopril | 2.5–5.0 q.d. | 20–35 q.d. |
| Ramipril | 2.5 q.d. | 5 b.i.d. |
| Trandolapril | 0.5 q.d. | 4 q.d. |
| Beta-blocker | ||
| Bisoprolol | 1.25 q.d. | 10 q.d. |
| Carvedilol a | 3.125 b.i.d. | 25–50 b.i.d. |
| Metoprolol succinate (CR/XL) | 12.5/25 q.d. | 200 q.d. |
| Nebivolol | 1.25 q.d. | 10 q.d. |
| ARB | ||
| Candesartan | 4 or 8 q.d. | 32 q.d. |
| Valsartan | 40 b.i.d. | 160 b.i.d. |
| Losartan | 50 q.d. | 150 q.d. |
| MRA | ||
| Eplerenone | 25 q.d. | 50 q.d. |
| Spironolactone | 25 q.d. | 25–50 q.d. |
b.i.d.=bis in die (twice daily); o.d.=omne in die (once daily); t.i.d.=ter in die (three times a day). Table adapted from. aA maximum dose of 50 mg twice daily can be administered to patients weighing over 85 kg. Abbreviations: b.i.d.=bis in die (twice daily); o.d.=omne in die (once daily); t.i.d.=ter in die (three times a day). ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; MRAs=mineralocorticoid receptor antagonist, BB=beta-blocker. ACC/AHA=American College of Cardiology (ACC)/American Heart Association (AHA), ESC=European Society of Cardiology
Supplemental Table S2.
Conversion of guideline directed medication dosage to equivalent doses
| ACEI | Dose | Ramipril |
|---|---|---|
| Captopril | 15 | 1 |
| Enalapril | 4 | 1 |
| Lisinopril | 4 | 1 |
| Perindopril | 1.6 | 1 |
|
| ||
| ARB | Dose | Candesartan |
|
| ||
| Irbesartan | 9.375 | 1 |
| Losartan | 4.6875 | 1 |
| Olmesartan | 1.25 | 1 |
| Telmisartan | 2.5 | 1 |
| Valsartan | 10 | 1 |
|
| ||
| BB | Dose | Carvedilol |
|
| ||
| Atenolol | 1 | 1 |
| Bisoprolol | 0.2 | 1 |
| Metoprolol | 2 | 1 |
| Nebivolol | 0.2 | 1 |
The ratio was determined by comparing the daily dose between the two drugs in the guidelines. ACEi converted to ramipril equivalent (RamEquiv). ARB converted to candesartan equivalent (CanEquiv). Beta blockers converted to carvedilol equivalent (CarvEquiv)
-
(i)
Dose equivalents: to facilitate analysis and permit comparison of the dosing strategies of the GDMT, each drug dose was converted to the equivalent daily dose of a selected representative drug as described in many previous reports and conversion tables.[40,41,42,43] Briefly, the dose of the angiotensin-converting enzyme inhibitors is converted to ramipril equivalents (RamiEquiv), the angiotensin receptor antagonists are converted to candesartan equivalent (CanEquiv), and beta blockers to carvedilol equivalents
-
(ii)
Target dosages: It is defined as the doses derived from the landmark trials or the maximum tolerated doses and were obtained from the American and European HF guidelines
-
(iii)
Dose optimization: It is the achievement of the target or the optimal dose for each GDMT drug. It is defined as the rate of the prescribed to the recommended dose for the different GDMT classes and was calculated for each patient and then, the percentages of the TD achievement for the GDMT classes among all patients were obtained.
TD-achievement of ≥100% guideline recommended TDs
Intermediate (optimal) dose-achievement of ≥50% (50%–99%) of recommended dose
Low (Suboptimal or sub-target) dose (<50% or 1%–49% of the recommended dose).
-
(iv)
Treatment intensity (number of GDMT drug classes prescribed): We calculated the proportion of patients prescribed monotherapy (use of 1 drug class, (RASi, BBs, or MRAs), dual therapy (use of 2 drug classes together (RASi + BB, RASi + MRA, βB + MRA), or triple therapy (conventional – use of all 3 drug classes together.[44]
Statistical analysis
Categorical (summarized using frequencies and percentages) and continuous normally distributed (presented using mean and standard deviation) variables were analyzed using Pearson’s χ2 test (or Fisher’s exact test for expected cells <5) and Student’s t-test, respectively. For continuous variables, we used measures of central tendency (mean and standard deviation) to summarize the data and analyzed using a t-test to compare the difference in means. The level of significance was set at P < 0.05. Statistical analysis was conducted using IBM SPSS Statistics for Windows, version 26 (IBM Corp., Armonk, N.Y., USA).
RESULTS
Patient characteristics
Among 1408 patients recruited in the current study, 65% were males, with a mean age of 53.5 ± 15.4 years, 34% were smokers, 58% chewing Katt, and 49% presented with de novo AHF. Coronary artery disease was the most prevalent, underlying disease (50%) and 21% had diabetes mellitus. Seventy-five percent were in NYHA class III/IV and volume overload was evident in the majority. More than half (53% n = 748) presented with HFrEF (EF <40%), 21% (n = 299), with HFpEF ((EF ≥50%), and 26% (n = 361) with HFmrEF (EF 40%-49%). Other baseline characteristics of the whole cohort and among the HF phenotypes are shown in Table 1.
Table 1.
Demographic, baseline, clinical and laboratory characteristics of acute heart failure patients stratified by the different heart failure groups
| Characteristics | EF (<40%) (n=748), n (%) | EF (40%–49%) (n=361), n (%) | EF (≥50%) (n=299), n (%) | All (n=1408), n (%) | P |
|---|---|---|---|---|---|
| Age (mean±SD) | 53.3±14.6 | 57.0±12.9 | 51.1±18.9 | 53.5±15.4 | |
| Male | 528 (70.6) | 259 (71.7) | 129 (43.1) | 916 (65.1) | 0.000 |
| Smoking | 266 (35.6) | 140 (38.8) | 72 (24.1) | 478 (33.9) | 0.001 |
| Chowing Katt | 454 (60.7) | 245 (67.9) | 114 (38.1) | 813 (57.7) | 0.000 |
| Admission for heart failure | 369 (49.3) | 94 (26.0) | 121 (40.5) | 584 (41.5) | 0.000 |
| Known systolic LV dysfunction | 348 (46.5) | 77 (21.3) | 16 (5.4) | 441 (31.3) | |
| Cardiologist | 551 (73.7) | 226 (62.6) | 238 (79.6) | 1015 (72.1) | 0.000 |
| CCU/ICU | 124 (16.6) | 136 (37.7) | 108 (36.1) | 368 (26.1) | 0.000 |
| Known CAD | 288 (38.5) | 189 (52.4) | 40 (13.4) | 517 (36.7) | 0.000 |
| HTN | 254 (34.0) | 168 (46.5) | 92 (30.8) | 514 (36.5) | 0.000 |
| VHD | 66 (8.8) | 23 (6.4) | 102 (34.1) | 191 (13.6) | 0.000 |
| Atrial fibrillation | 41 (5.5) | 8 (2.2) | 30 (10.0) | 79 (5.6) | 0.000 |
| DM | 132 (17.7) | 107 (29.6) | 63 (21.0) | 302 (21.4) | |
| Hyperlipidemia | 93 (12.4) | 49 (13.6) | 6 (2.0) | 148 (10.5) | 0.000 |
| Asthma/COPD | 3 (0.4) | 8 (2.2) | 50 (16.7) | 61 (4.3) | 0.000 |
| CKD/dialysis | 10 (1.3) | 6 (1.7) | 5 (1.7) | 21 (1.5) | 0.878 |
| PVD | 11 (1.5) | 11 (3.0) | 7 (2.3) | 29 (2.1) | 0.207 |
| Stroke/TIA | 38 (5.1) | 13 (3.6) | 10 (3.3) | 61 (4.3) | 0.336 |
| ADHF | 432 (57.8) | 121 (33.5) | 166 (55.5) | 719 (51.1) | |
| New-onset HF | 316 (42.2) | 240 (66.5) | 133 (44.5) | 689 (48.9) | |
| NYHA III–IV | 616 (82.3) | 228 (63) | 211 (70.5) | 1059 (75.3) | |
| Orthopnea | 659 (88.1) | 248 (68.7) | 255 (85.3) | 1162 (82.5) | 0.000 |
| PND | 629 (84.1) | 236 (65.4) | 218 (72.9) | 1083 (76.9) | |
| LL swelling | 545 (72.90) | 125 (34.60) | 184 (61.50) | 854 (60.70) | 0.000 |
| HR, mean±SD | 104.2±18.2 | 93.5±22.4 | 98.3±24.6 | 100.2±21.3 | |
| SBP (mmHg) | 131.7±32.2 | 136.3±27.1 | 125.1±29.6 | 131.5±30.6 | |
| DBP (mmHg) | 83.3±19.5 | 84.7±16.3 | 76.6±17.0 | 82.3±18.4 | |
| BMI (kg/m2), mean±SD | 25.7±4.0 | 26.2±4.4 | 25.5±5.2 | 25.8±4.4 | 0.077 |
| Raised JVP* | 530 (70.90) | 161 (44.60) | 189 (63.20) | 880 (62.50) | 0.000 |
| LL oedema | 565 (75.5) | 144 (39.9) | 200 (66.9) | 909 (64.6) | |
| Enlarged tender liver | 522 (69.8) | 132 (36.6) | 186 (62.2) | 840 (59.7) | |
| Gallop | 518 (69.30) | 150 (41.60) | 122 (40.80) | 790 (56.10) | 0.000 |
| Basal crepitations | 722 (96.50) | 343 (95.00) | 269 (90.00) | 1334 (94.7) | |
| Signs of PE | 280 (37.40) | 73 (20.20) | 84 (28.10) | 437 (31.00) | 0.000 |
| High troponin-I/T | 73±9.8 | 112±31.0 | 63±21.1 | 248±17.6 | |
| Hg (g/dL), mean±SD | 12.7±2.4 | 14.0±2.6 | 13.3±2.7 | 13.1±2.6 | 0.000 |
| Urea (mg%) | 44.20±24.71 | 31.19±22.97 | 30.04±19.87 | 37.86±24.26 | |
| Creatinine (mg/dL) | 1.305±0.9090 | 1.124±0.9178 | 1.123±1.1752 | 1.220±0.9772 | |
| e-GFR (mL/min), mean±SD | 70.2±32.6 | 86.0±41.0 | 87.1±46.2 | 77.8±38.9 | 0.000 |
| PASP (mmHg) | 55.0±15.4 | 53.1±17.5 | 71.2±25.5 | 58.8±20.4 | 0.000 |
*Raised (>6 cm) JVP. LV: Left ventricular, EF: Ejection fraction, CCU/ICU: Coronary care unit/intensive care unit, CAD: Coronary artery disease, HTN: Hypertension, VHD: Valvular heart disease, COPD: Chronic obstructive pulmonary disease, CKD: Chronic kidney disease, PVD: Peripheral artery disease, TIA: Transient ischemic attack, ADHF: Acute decompensated heart failure, NYHA: New York Heart Association, PND: Paroxysmal nocturnal dyspnea, LL: Lower limb, HR: Heart rate, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, BMI: Body mass index, JVP: Jugular venous pressure, Hg: Hemoglobin, eGFR: Estimated glomerular filtration rate, PASP: Pulmonary artery systolic pressure, PE: Pleural effusion, SD: Standard deviation, DM: Diabetes mellitus
Guideline-directed medical therapy
Overall guideline-directed medical therapy prescription and drug characteristics
As shown in Table 2, at baseline, out of the entire cohort (n = 1408), 28.4% (n = 400) were on BBs; 51% (n = 716) were on RASi [47.7% on ACEi and 3.2% on ARB], and only 10% (n = 143) on spironolactone, while on discharge, 69.5% (n = 978) on BB, 82% (n = 1157) on RASi (69% ACEi and 12.8% ARBs), and 59.0% (n = 831) on spironolactone. Bisoprolol was the most frequently used BB on admission (53% n = 211) and discharge 55% (n = 539), with a mean carvedilol equivalent daily dose of 13.24 mg on admission vs. 16.128 mg on discharge.
Table 2.
Pre-admission and on discharge medications of acute heart failure patients stratified by the different heart failure groups
| Pharmacological class | EF (<40%) (n=748), n (%) | EF (40%–49%) (n=361), n (%) | EF (≥50%) (n=299), n (%) | All (n=1408), n (%) | P |
|---|---|---|---|---|---|
| Digoxin | |||||
| Before admission | 211 (28.2) | 23 (6.4) | 58 (19.4) | 292 (20.7) | 0.000 |
| On discharge | 344 (46.0) | 54 (15.0) | 48 (16.1) | 446 (31.7) | 0.000 |
| Calcium blockers | |||||
| Before admission | 10 (1.3) | 13 (3.6) | 39 (13.0) | 62 (4.4) | 0.000 |
| On discharge | 7 (0.9) | 18 (5.0) | 49 (16.4) | 74 (5.3) | 0.000 |
| Aspirin | |||||
| Before admission | 429 (57.4) | 236 (65.4) | 86 (28.8) | 751 (53.3) | 0.000 |
| On discharge | 565 (75.5) | 324 (89.8) | 180 (60.2) | 1069 (75.9) | 0.000 |
| Clopidogrel | |||||
| Before admission | 69 (9.2) | 92 (25.5) | 10 (3.3 | 171 (12.1) | 0.000 |
| On discharge | 181 (24.2) | 220 (60.9) | 71 (23.7) | 472 (33.5) | 0.000 |
| Statins | |||||
| Before admission | 195 (26.1) | 138 (38.2) | 27 (9.0) | 360 (25.6) | 0.000 |
| On discharge | 359 (48.0) | 267 (74.0) | 94 (31.4) | 720 (51.1) | 0.000 |
| Diuretics | |||||
| Before admission | 369 (49.3) | 123 (34.1) | 150 (50.2) | 642 (45.6) | 0.000 |
| On discharge | 691 (92.4) | 324 (89.8) | 233 (77.9) | 1248 (88.6) | 0.000 |
| Oral nitrates | |||||
| Before admission | 125 (16.7) | 58 (16.1) | 6 (2.0) | 189 (13.4) | 0.000 |
| On discharge | 211 (28.2) | 95 (26.3) | 22 (7.4) | 328 (23.3) | 0.000 |
| Oral anticoagulants | |||||
| Before admission | 86 (11.5) | 13 (3.6) | 37 (12.4) | 136 (9.7) | 0.000 |
| On discharge | 152 (20.3) | 38 (10.5) | 60 (20.1) | 250 (17.8) | 0.000 |
| Heparin/LMWH | |||||
| Before admission | 1 (0.1) | 4 (1.1) | 3 (1.0) | 8 (0.6) | 0.068 |
| Inhospital | 6 (0.8) | 5 (1.4) | 1 (0.3) | 12 (0.9) | 0.335 |
LMWH: Low-molecular-weight heparin, EF: Ejection fraction
Uses of guideline-directed medical therapy in heart failure phenotypes
Concerning the different HF types, results in Table 3 showed that on admission using BBs, RAAS blockers, and MRAs were 29%, 58%, and 15.8% in HFrEF, 40%, 56.5%, and 3.6% in HFmrEF and 12.7%, 25%, and 4% in HFpEF, respectively. While on discharge using BBs, RASi, and MRAs were 76%, 90%, and 79% in HFrEF, 79.2%, 86.7%, and 36.6% in HFmrEF, and 41.1%, 57%, and 35.8% in HFpEF, respectively. The most commonly used BBs on admission and discharge were carvedilol in HFrEF and bisoprolol in both HFmrEF and HFpEF. Lisinopril was the most common RASi used on admission and discharge in HFrEF, HFmrEF, and HFpEF.
Table 3.
Use, dosage, and characteristics of guideline-directed medical therapy medications on admission and discharge of acute heart failure patients stratified by the different heart failure groups
| Drug | EF (<40%) (n=748) | EF (40%–49%) (n=361) | EF (≥50%) (n=299) | All (n=1408) | P |
|---|---|---|---|---|---|
| Use of BBs, n (%) | |||||
| Before admission | 216 (28.9) | 146 (40.4) | 38 (12.7) | 400 (28.4) | 0.000 |
| On discharge BB | 569 (76.1) | 286 (79.2) | 123 (41.1) | 978 (69.5) | 0.000 |
| Preadmission BBs, n (%) | |||||
| Carvedilol | 104 (13.9) | 25 (6.9) | 4 (1.3) | 133 (9.4) | 0.000 |
| Bisoprolol | 95 (12.7) | 90 (24.9) | 26 (8.7) | 211 (15.0) | 0.000 |
| Metoprolol | 9 (1.2) | 16 (4.4) | 3 (1.0) | 28 (2.0) | 0.000 |
| On discharge BBs, n (%) | |||||
| Carvedilol | 319 (42.6) | 63 (17.5) | 8 (2.7) | 390 (27.7 | 0.000 |
| Bisoprolol | 234 (31.3) | 202 (56.0) | 103 (34.4) | 539 (38.3) | 0.000 |
| Metoprolol | 16 (2.1) | 16 (4.4) | 11 (3.7) | 43 (3.1) | 0.000 |
| BBs dose, mean±SD | |||||
| Carvedilol | |||||
| Admission - dose | 4.99±2.02 | 5.75±1.17 | 5.47±1.56 | 5.15±1.89 | 0.184 |
| Discharge - dose | 5.14±2.02 | 5.56±1.90 | 6.25±0.00 | 5.23±1.99 | 0.111 |
| Bisoprolol | |||||
| Admission - dose | 3.47±1.23 | 3.47±1.32 | 3.13±1.19 | 3.43±1.26 | 0.423 |
| Discharge - dose | 4.36±2.46 | 3.85±1.41 | 3.40±1.21 | 3.98±1.94 | 0.000 |
| Metoprolol | |||||
| Admission - dose | 38.89±13.18 | 34.38±12.50 | 25.00±0.00 | 34.82±12.43 | 0.247 |
| Discharge - dose | 41.41±13.48 | 50.78±44.83 | 47.73±20.78 | 46.51±30.05 | 0.680 |
| Use of ACEi, n (%) | |||||
| Preadmission ACE | 412 (55.1) | 188 (52.1) | 71 (23.7) | 671 (47.7) | 0.000 |
| On discharge ACEi | 551 (73.7) | 275 (76.2) | 151 (50.5) | 977 (69.4) | 0.000 |
| Before admission ACEi, n (%) | |||||
| Captopril | 112 (15.0) | 47 (13.0) | 14 (4.7) | 173 (12.3) | 0.000 |
| Lisinopril | 224 (29.9) | 108 (29.9) | 47 (15.7) | 379 (26.9) | 0.000 |
| Enalapril | 29 (3.9) | 12 (3.3) | 5 (1.7) | 46 (3.3) | 0.000 |
| Ramipril | 45 (6.0) | 20 (5.5) | 5 (1.7) | 70 (5.0) | 0.000 |
| On discharge ACEi, n (%) | |||||
| Captopril | 98 (13.1) | 39 (10.8) | 15 (5.0) | 152 (10.8) | 0.000 |
| Lisinopril | 279 (37.3) | 169 (46.8) | 104 (34.8) | 552 (39.2) | 0.000 |
| Enalapril | 58 (7.8) | 25 (6.9) | 13 (4.3) | 96 (6.8) | 0.000 |
| Ramipril | 115 (15.4) | 41 (11.4) | 19 (6.4) | 175 (12.4) | 0.000 |
| ACEi dose, mean±SD | |||||
| Captopril | |||||
| Admission - dose | 12.30±7.33 | 19.81±7.85 | 20.54±14.17 | 15.01±8.94 | 0.000 |
| Discharge - dose | 12.88±6.67 | 15.06±6.20 | 13.75±4.84 | 13.53±6.43 | 0.240 |
| Lisinopril | |||||
| Admission - dose | 4.19±2.25 | 4.35±2.25 | 4.89±2.44 | 4.32±2.28 | 0.152 |
| Discharge - dose | 4.90±3.50 | 5.39±3.31 | 5.14±3.25 | 5.10±3.40 | 0.340 |
| Enalapril | |||||
| Admission - dose | 7.16±4.52 | 11.25±7.03 | 14.50±7.98 | 9.02±6.11 | 0.012 |
| Discharge - dose | 9.01±6.10 | 13.50±7.25 | 8.46±5.82 | 10.10±6.64 | 0.100 |
| Ramipril | |||||
| Admission - dose | 3.11±1.76 | 3.13±1.11 | 3.00±1.12 | 3.11±1.55 | 0.987 |
| Discharge - dose | 3.79±2.32 | 3.57±1.62 | 3.42±1.90 | 3.70±2.13 | 0.704 |
| Use of ARBs, n (%) | |||||
| Before admission | 25 (3.3) | 16 (4.4) | 4 (1.3) | 45 (3.2) | 0.075 |
| On discharge | 122 (16.3) | 38 (10.5) | 20 (6.7) | 180 (12.8) | 0.000 |
| Before admission ARBs, n (%) | |||||
| Valsartan | 6 (0.8) | 2 (0.6) | 0 | 8 (0.6) | 0.156 |
| Candesartan | 8 (1.1) | 5 (1.4) | 2 (0.7) | 15 (1.1) | 0.245 |
| Losartan | 11 (1.5) | 9 (2.5) | 2 (0.7) | 22 (1.6) | 0.206 |
| On discharge ARBs, n (%) | |||||
| Valsartan | 5 (0.70) | 7 (1.90) | 5 (1.70) | 17 (1.20) | 0.000 |
| Candesartan | 77 (10.30) | 12 (3.30) | 6 (2.00) | 95 (6.70) | 0.000 |
| Losartan | 39 (5.20) | 17 (4.70) | 8 (2.70) | 64 (4.50) | 0.000 |
| ARBs dose, mean±SD | |||||
| Valsartan | |||||
| Admission - dose | 46.67±16.33 | 60.00±28.28 | NA | 50.00±18.52 | 0.420 |
| Discharge - dose | 48.00±17.89 | 91.43±30.24 | 80.00±48.99 | 75.29±37.10 | 0.125 |
| Candesartan | |||||
| Admission - dose | 6.00±4.28 | 9.60±6.07 | 6.00±2.83 | 7.20±4.83 | 0.427 |
| Discharge - dose | 10.70±7.06 | 7.67±4.33 | 8.00±4.38 | 10.15±6.70 | 0.250 |
| Losartan | |||||
| Admission - dose | 50.00±0.00 | 36.11±13.18 | 37.50±17.68 | 43.18±11.40 | 0.011 |
| Discharge - dose | 46.79±8.47 | 45.59±9.82 | 46.88±8.84 | 46.48±8.76 | 0.889 |
| Use of MRAs, n (%) | |||||
| Before admission | 118 (15.8) | 13 (3.6) | 12 (4.0) | 143 (10.2) | 0.000 |
| On discharge | 592 (79.1) | 132 (36.6) | 107 (35.8) | 831 (59.0) | 0.000 |
| MRAs dose, mean±SD | |||||
| Admission – dose | 26.7±6.3 | 28.8±9.4 | 30.7±23.3 | 27.2±9.0 | 0.293 |
| Discharge – dose | 27.2±8.4 | 29.5±11.2 | 32.8±11.6 | 28.2±9.5 | 0.000 |
SD: Standard deviation, BBs: Beta-blockers, ACE: Angiotensin-converting enzyme, ARBs: Angiotensin receptor blockers, MRAs: Mineralocorticoid receptor antagonists, EF: Ejection fraction, ACEi: ACE inhibitors, NA: Not available
Guideline-directed medical therapy dose achievement and optimization
Guideline-directed medical therapy combination therapy-treatment intensity in heart failure with reduced ejection fraction
At baseline, only 10% (n = 74) of patients with HFrEF were on the recommended triple combination GDMT therapy, 19% (n = 144) on dual therapy, (mostly of ACEi and BBs), 34.8% (n = 260) were on only one GDMT drug (mostly ACEi), and 36% (n = 270) were not receiving any GDMT drug. On the other hand, 61.5% (n = 460) were discharged on triple therapy, 28% (N = 209) on dual therapy, 4% (n = 33) on monotherapy, and 6% (n = 45) were not receiving any GDMT drug. For more details see Figure 1.
Figure 1.
The proportion of patients prescribed Combination guideline-directed medical therapy-treatment intensity among patients with heart failure with reduced ejection fraction. †GDMT: Guideline-Directed Medical Therapies that include four classes of drugs; renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), evidence-based beta-blockers (BBs) and mineralocorticoid receptor antagonist (MRA). *monotherapy (defined as the use of 1 drug class, (RASi, BBs, or MRAs), dual therapy (use of 2 drug classes together (RASi + BB, RASi + MRA, or BB + MRA), triple therapy defined as the use of all 3 drug classes together
Target (i.e., ≥100% of target dose) dose achievement on admission and discharge
As illustrated in Figure 1, at the time of admission, among 400 patients on BBs, no patient prescribed the TD, while among 716 patients on RASi, only 2 patients (0.3%) prescribed the TD. On discharge, among 978 patients discharged on BBs, only 3.6% (N = 35) were prescribed the TD and 1157 patients discharged on RASi, 1.5% (n = 17) patients received the TD of either ACEi or ARBs.
Optimal dose achievement (i.e., ≥50% of target dose)
The proportion of patients prescribed the optimal dose of BB and RAAS blockers were, respectively, 22.5% and 6.28% at the time of admission and 28% and 13.1% on discharge. For more details see Table 4.
Table 4.
The proportion of patients prescribed the target dose (i.e. ≥100% of the target dose), the optimal dose (i.e. ≥50% of the target dose/day), or suboptimal dose (i.e. <50% of target dose/day) on admission and discharge regardless of ejection fraction
| Drug | Time of prescription | Number of patients | Proportion of TD*,† |
||
|---|---|---|---|---|---|
| <50%, n (%) | 50%–<100%, n (%) | ≥100%, n (%) | |||
| BBs | Admission | 372 | 282 (75.8) | 90 (24.2) | 0 |
| Discharge | 972 | 663 (68) | 274 (28) | 35 (3.6) | |
| Carvedilol | Admission | 133 | 100 | 0 | 0 |
| Discharge | 390 | 382 (97.9) | 8 (2) | 0 | |
| Bisoprolol | Admission | 211 | 130 (61.6) | 81 (38) | |
| Discharge | 539 | 264 (49) | 243 (45) | 32 (5.9) | |
| Metoprolol | Admission | 28 | 19 (67.9) | 9 (32.1) | 0 |
| Discharge | 43 | 17 (39.5) | 23 (53.5) | 3 (6.97) | |
| RAS blockers | Admission | 713 | 666 (93.6) | 45 (6.1) | 2 (0.28) |
| Discharge | 1151 | 982 (85.3) | 152 (13.1) | 17 (1.5) | |
| Captopril | Admission | 173 | 155 (89.6) | 18 (10.4) | 1 |
| Discharge | 152 | 145 (95.4) | 7 | 0 | |
| Lisinopril | Admission | 379 | 378 (99.7) | 1 | 0 |
| Discharge | 552 | 529 (95.8) | 22 (3.98) | 1 | |
| Ramipril | Admission | 70 | 56 (80) | 12 (17.1) | 1 |
| Discharge | 175 | 99 (56.6) | 57 (32.6) | 13 (7.4) | |
| Enalapril | Admission | 46 | 36 (78.2) | 10 (21.7) | 0 |
| Discharge | 96 | 68 (70.8) | 28 (29.2) | 0 | |
| Candesartan | Admission | 15 | 12 (80) | 3 (20) | 0 |
| Discharge | 95 | 56 (58.9) | 36 (37.9) | 3 (3.15) | |
| Losartan | Admission | 22 | 21 (95.5) | 1 | 0 |
| Discharge | 64 | 64 (100) | 0 | 0 | |
| Valsartan | Admission | 8 | 8 (100) | 0 | 0 |
| Discharge | 17 | 15 (88.2) | 2 (11.8) | 0 | |
*TD of BBs ≥25 mg/day for carvedilol, ≥10 mg/day bisoprolol and ≥200 mg/day metoprolol CR/XL), †TD (i.e. ≥100% of the TD), optimal dose (i.e. ≥50% and <100% of the TD/day) or suboptimal dose (i.e. <50% of TD/day). TRGET dose of RAS blockers (i.e. ≥150 mg/day captopril, ≥40 mg/day for lisinopril and enalapril, ≥10 mg/day for ramipril, ≥32 mg/day candesartan, ≥150 mg/day for losartan and ≥320 mg/day for valsartan. RAS blockers: Renin angiotensin system blockers, TD: Target dose, BBs: Beta-blockers, Metoprolol succinate extended release (metoprolol CR/XL)
DISCUSSION
To the best of our knowledge, no prior data on dose optimization of GDMT among acute HF patients in Yemen, therefore, we present the first comprehensive study on this issue in a large cohort of AHF patients comparing preadmission to discharge data. A new aspect in this study is the extension to the EF-based HF categories.
The main findings
There are a number of important findings in the present study.
Significant variation in prescription of baseline and discharge medications among the different HF phenotypes including the GDMT
Implementation Gap; underutilization of GDMT at baseline particularly triple therapy
Extremely low rate of Target and Optimal Dose Achievement both on admission and at discharge.
Medications prescription and its variation across the heart failure phenotypes
As reported by several national and international reports, we found significant differences in the prescription pattern among the HF phenotypes. Both antiplatelets and statins were prescribed more to HFmrEF, digoxin prescribed more to HFrEF, and calcium channel blockers (CCB) were prescribed more to HFpEF findings consistent with several national and international registries.[45,46,47,48,49,50,51] With respect to GDMT, we found a comparable baseline use of BB and RAS blockers in HFrEF and HFmrEF (P < 0.001), and higher MRA use in HFrEF, a finding similarly reached by the Gulf CARE registry[52] and by other national data from Oman,[46] and KSA,[47] among other registries.[49,52,53]
Low adherence to guidelines-implementation gap
Implementation of GDMT, as per the guidelines and consensus documents, entails full use of GDMT drugs, combination GDMT therapy, and TD achievement. The most important and disappointing finding in our study is the poor implementation of GDMT with respect to the following; (1) GDMT underuse at baseline, (2) low prescription of the recommended triple combination GDMT therapy, and (3) poor TD achievement.
Although our data showed a reasonable discharge GDMT prescription to HFrEF: RASi (90%), BBs (76%), and MRA (79%), a pattern similar to other AHF registries,[23,45,46,47,48,49,50,51] yet the considerably low baseline GDMT use, particularly for BBs and MRAs [RASi, (58%); BBs, (29%), and MRAs, (16%)], and 36% were not receiving any GDMT, is a challenge and is considered a major implementation gap. Many national data[46,52,54] reported a much higher use of GDMT at baseline, for example, Jan et al.[52] reported an 80% RASi, 75% BB, and 56% on MRAs and only 7.5% were not on any GBMT.
Only 10% of our patients were on triple therapy, compared to 39% and 33% from other national registries,[46,52] and 34%–69% in international cohorts.[55] Recent data from the GWTG-HF registry found that 14.9% of eligible patients were receiving all medications on admission,[56] among others.[57] Multiple scientific evidences have demonstrated the progressive and incremental benefits of drug combinations with greater reductions in mortality and hospitalizations with triple than dual or single therapy.[6,23,44,58,59,60]
There is robust evidence supporting the dose-dependent benefit of GDMT, with over three-fold greater risk in those on low doses and greater risk with dose de-escalation.[61,62] The highest and lowest rates of mortality in CHAMP-HF were seen in those on <50% and those on TD, respectively.[63] TD attainment is a worldwide problem, for example, RASi 13%, BBs 7.3%, and MRAs 14% in the Gulf CARE registry and RASi 13%, BB 27%, and MRA 4.4% in Gulf DYSPNEA. At the international level, many reports found similar results.[15,64,65] On international level TD attainment was also not satisfactory for example the percentage of TD achieved were 27.9% for ACEi, 6.9% for ARBs; and 14.8% for BB; in QUALIFY,[13] 17%, for ACEi/ARB, 13%, for BB, in ASIAN-HF registry[66] and 22% for ACEI/ARBs, and 12% for BB in BIOSTAT-CHF.[67]
In our cohort, TD achievement at baseline was 0% for BBs and 0.279% (n = 2) RAS blockers, which is very low compared to national and international data, and did not significantly improve by time of discharge (3.6% (N = 35) for BB and 1.5% (n = 17) for RAS blockers. Furthermore, although the abovementioned studies reported low TD achievement, yet attainment of optimal dose (i. e. ≥50% of TD) was good. Data from Oman showed low TD attainment for BBs 16.5% and RASi 3.6%, but good attainment of optimal dose (57% and 44% for, respectively, BB, and ACEIs/ARBs. Similarly, high rate of patients at ≥50% TD in QUALIFY[27] (63.3% for ACEIs; 39.5% for ARBs; 51.8% for BB; and 99.1% for MRAs) and BIOSTAT-CHF[67] (53% for ACEI/ARBs, and 40% for BB).
Unfortunately, the most alarming and disappointing message in the present study is the extremely low rate of optimal dose (i. e. ≥50% of TD) achievement both on admission (22.5% of BBs and 6.8% of RASi) and on discharge (28% of BBs and 13.1% of RASi). Considering that medications taken by the patient before presentation to the hospital represent the actual clinical practice in the outpatient setting, 71% and 93% of patients were on suboptimal doses (<50% of the TD) of BBs and RAAS blockers, respectively. It has been reported that patients receiving <50% of recommended doses had worse survival.[67]
More alarming message was that despite sufficient hospital time, 68% and 85% of patients were discharged on suboptimal doses of BBs and RAAS blockers, respectively. Therefore, among HF patients (more than half with HFrEF who gain the maximal benefits of TD), our results revealed an extremely poor dose optimization in Yemen. Although poor GDMT implementation is multifactorial, clinical, or therapeutic inertia, defined as a hesitancy to make changes, or to modify therapy according to guidelines, when clinically indicated appears to be at least one major factor.[68,69] Multiple reasons can lead to therapeutic inertia: patient apparent stability, physician lack of time, training, and poor awareness of recent therapeutic developments.[69] Age and insurance status may not totally explain the suboptimal treatment of HFrEF patients.[70] Reasons may not clearly obvious in patients’ medical notes.[71] Other clinical reasons include renal impairment, hypotension, and hyperkalemia.[55,72]
Limitations
There are some limitations to the current study. First, the study enrolment period (2012) was conducted before the inclusion of new drugs to the GDMT as ARNis and SGLT-2 inhibitors thus these were missing. However, recently published few data on AHF in the region also did not mention these newer GBMT modalities.[46,52,64] Second, as GBMT doses were reported in an inpatient setting, the reported underdosing may be inaccurate, since uptitration of the doses usually occurs in the outpatient setting. Third, the study design was retrospective; therefore, it may have inherently introduced self-selection biases. Fourth, the unavailability of certain data as the compliance to GDMT medications before hospital admission, as well as details about side effects and contraindications to certain medications which may have led to lower utilization of GBMT. Fifth, as nearly half of our cohort (48.9%) presented with de novo HF, the reported underdosing may be inaccurate, since it is expected that these patients will not be on GDMT on admission. Sixth, given that GBMT dosages were reported in an inpatient setting, the reported underdosing may be inaccurate, since uptitration of the doses usually occurs in the outpatient setting” similar to the Gulf CARE registry report.
CONCLUSIONS AND RECOMMENDATIONS
The current data showed poor GDMT implementation among HFrEF patients in Yemen with considerably low prescriptions of GDMT, especially BBs, and MRAs, with one-third of patients were not receiving any GDMT, and only 10% on triple GDMT therapy at the time of admission. The GDMT prescription at the time of discharge can be considered acceptable. Nonetheless, the prescribing of triple therapy for HFrEF in Yemen was underutilized. However, the most alarming message in the present study is the extremely low rate of TD achievement. These substantial gaps in practice related to guideline-recommended dosing of medications in Yemen require multiple initiatives to facilitate increased implementation of guideline-recommended prescribing and evidence-based dosing, encouraging timely uptitration to TDs in patients with HFrEF. Such initiatives include continuing education and team-based care approaches including a pharmacist may improve initiation, uptitration, and compliance to medication of HF patients. A lot of essential efforts to improve GDMT utilization must be undertaken one of which is to provide equitable access to the cost-effective foundational therapies for HFrEF. Physicians’ knowledge and practice toward GDMT implementations is another important issue that should take priority from healthcare systems. Further studies are warranted to explore why Yemeni physicians are reluctant to uptitrate medications to target tolerated doses, other factors associated with GDMT underutilization and suboptimal dosing in the outpatient settings, and the impact of guidelines nonadherence with respect to underutilization and suboptimal dosing terms of mortality and hospitalization risk in our country. These findings can guide targeted efforts toward achieving improved clinical practice.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
REFERENCES
- 1.Biegus J, Moayedi Y, Saldarriaga C, Ponikowski P. Getting ahead of the game: In-hospital initiation of HFrEF therapies. Eur Heart J Suppl. 2022;24:L38–44. doi: 10.1093/eurheartjsupp/suac120. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Davidson BT, Dunham S. The perfect storm: Barriers to heart failure treatment optimization. Crit Care Nurs Clin North Am. 2022;34:141–50. doi: 10.1016/j.cnc.2022.02.003. [DOI] [PubMed] [Google Scholar]
- 3.Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–200. doi: 10.1093/eurheartj/ehw128. [DOI] [PubMed] [Google Scholar]
- 4.McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–726. doi: 10.1093/eurheartj/ehab368. [DOI] [PubMed] [Google Scholar]
- 5.Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79:e263–421. doi: 10.1016/j.jacc.2021.12.012. [DOI] [PubMed] [Google Scholar]
- 6.Vaduganathan M, Claggett BL, Jhund PS, Cunningham JW, Pedro Ferreira J, Zannad F, et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: A comparative analysis of three randomised controlled trials. Lancet. 2020;396:121–8. doi: 10.1016/S0140-6736(20)30748-0. [DOI] [PubMed] [Google Scholar]
- 7.Ouwerkerk W, Teng TK, Tromp J, Tay WT, Cleland JG, van Veldhuisen DJ, et al. Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction: Insights from BIOSTAT-CHF and ASIAN-HF registries. Eur J Heart Fail. 2020;22:1472–82. doi: 10.1002/ejhf.1869. [DOI] [PubMed] [Google Scholar]
- 8.Writing Committee , Maddox TM, Januzzi JL, Jr., Allen LA, Breathett K, Butler J, et al. 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: Answers to 10 pivotal issues about heart failure with reduced ejection fraction: A report of the American College of Cardiology solution set oversight committee. J Am Coll Cardiol. 2021;77:772–810. doi: 10.1016/j.jacc.2020.11.022. [DOI] [PubMed] [Google Scholar]
- 9.Savarese G, Bodegard J, Norhammar A, Sartipy P, Thuresson M, Cowie MR, et al. Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: A multinational observational study (US, UK and Sweden) Eur J Heart Fail. 2021;23:1499–511. doi: 10.1002/ejhf.2271. [DOI] [PubMed] [Google Scholar]
- 10.Tsigkas G, Apostolos A, Aznaouridis K, Despotopoulos S, Chrysohoou C, Naka KK, et al. Real-world implementation of guidelines for heart failure management: A systematic review and meta-analysis. Hellenic J Cardiol. 2022;66:72–9. doi: 10.1016/j.hjc.2022.04.006. [DOI] [PubMed] [Google Scholar]
- 11.Bhagat AA, Greene SJ, Vaduganathan M, Fonarow GC, Butler J. Initiation, continuation, switching, and withdrawal of heart failure medical therapies during hospitalization. JACC Heart Fail. 2019;7:1–12. doi: 10.1016/j.jchf.2018.06.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Gilstrap LG, Fonarow GC, Desai AS, Liang L, Matsouaka R, DeVore AD, et al. Initiation, continuation, or withdrawal of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and outcomes in patients hospitalized with heart failure with reduced ejection fraction. J Am Heart Assoc. 2017;6:e004675. doi: 10.1161/JAHA.116.004675. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Greene SJ, Fonarow GC, DeVore AD, Sharma PP, Vaduganathan M, Albert NM, et al. Titration of medical therapy for heart failure with reduced ejection fraction. J Am Coll Cardiol. 2019;73:2365–83. doi: 10.1016/j.jacc.2019.02.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Greene SJ, Butler J, Albert NM, DeVore AD, Sharma PP, Duffy CI, et al. Medical therapy for heart failure with reduced ejection fraction: The CHAMP-HF registry. J Am Coll Cardiol. 2018;72:351–66. doi: 10.1016/j.jacc.2018.04.070. [DOI] [PubMed] [Google Scholar]
- 15.Savarese G, Kishi T, Vardeny O, Adamsson Eryd S, Bodegård J, Lund LH, et al. Heart failure drug treatment-inertia, titration, and discontinuation: A multinational observational study (EVOLUTION HF) JACC Heart Fail. 2023;11:1–14. doi: 10.1016/j.jchf.2022.08.009. [DOI] [PubMed] [Google Scholar]
- 16.Butler J, Yang M, Manzi MA, Hess GP, Patel MJ, Rhodes T, et al. Clinical course of patients with worsening heart failure with reduced ejection fraction. J Am Coll Cardiol. 2019;73:935–44. doi: 10.1016/j.jacc.2018.11.049. [DOI] [PubMed] [Google Scholar]
- 17.Bragazzi NL, Zhong W, Shu J, Abu Much A, Lotan D, Grupper A, et al. Burden of heart failure and underlying causes in 195 countries and territories from 1990 to 2017. Eur J Prev Cardiol. 2021;28:1682–90. doi: 10.1093/eurjpc/zwaa147. [DOI] [PubMed] [Google Scholar]
- 18.Urbich M, Globe G, Pantiri K, Heisen M, Bennison C, Wirtz HS, et al. A systematic review of medical costs associated with heart failure in the USA (2014-2020) Pharmacoeconomics. 2020;38:1219–36. doi: 10.1007/s40273-020-00952-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Greene SJ, Fonarow GC, Vaduganathan M, Khan SS, Butler J, Gheorghiade M. The vulnerable phase after hospitalization for heart failure. Nat Rev Cardiol. 2015;12:220–9. doi: 10.1038/nrcardio.2015.14. [DOI] [PubMed] [Google Scholar]
- 20.Yamaguchi T, Kitai T, Miyamoto T, Kagiyama N, Okumura T, Kida K, et al. Effect of optimizing guideline-directed medical therapy before discharge on mortality and heart failure readmission in patients hospitalized with heart failure with reduced ejection fraction. Am J Cardiol. 2018;121:969–74. doi: 10.1016/j.amjcard.2018.01.006. [DOI] [PubMed] [Google Scholar]
- 21.Yoshioka K, Matsue Y, Yamaguchi T, Kitai T, Kagiyama N, Okumura T, et al. Safety and prognostic impact of early treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with acute heart failure. Am J Cardiovasc Drugs. 2019;19:597–605. doi: 10.1007/s40256-019-00355-3. [DOI] [PubMed] [Google Scholar]
- 22.Busson A, Thilly N, Laborde-Castérot H, Alla F, Messikh Z, Clerc-Urmes I, et al. Effectiveness of guideline-consistent heart failure drug prescriptions at hospital discharge on 1-year mortality: Results from the EPICAL2 cohort study. Eur J Intern Med. 2018;51:53–60. doi: 10.1016/j.ejim.2017.12.005. [DOI] [PubMed] [Google Scholar]
- 23.Gayat E, Arrigo M, Littnerova S, Sato N, Parenica J, Ishihara S, et al. Heart failure oral therapies at discharge are associated with better outcome in acute heart failure: A propensity-score matched study. Eur J Heart Fail. 2018;20:345–54. doi: 10.1002/ejhf.932. [DOI] [PubMed] [Google Scholar]
- 24.Mebazaa A, Davison B, Chioncel O, Cohen-Solal A, Diaz R, Filippatos G, et al. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): A multinational, open-label, randomised, trial. Lancet. 2022;400:1938–52. doi: 10.1016/S0140-6736(22)02076-1. [DOI] [PubMed] [Google Scholar]
- 25.Brownell NK, Ziaeian B, Fonarow GC. The gap to fill: Rationale for rapid initiation and optimal titration of comprehensive disease-modifying medical therapy for heart failure with reduced ejection fraction. Card Fail Rev. 2021;7:e18. doi: 10.15420/cfr.2021.18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.DeVore AD, Thomas L, Albert NM, Butler J, Hernandez AF, Patterson JH, et al. Change the management of patients with heart failure: Rationale and design of the CHAMP-HF registry. Am Heart J. 2017;189:177–83. doi: 10.1016/j.ahj.2017.04.010. [DOI] [PubMed] [Google Scholar]
- 27.Komajda M, Anker SD, Cowie MR, Filippatos GS, Mengelle B, Ponikowski P, et al. Physicians – Adherence to guideline-recommended medications in heart failure with reduced ejection fraction: Data from the QUALIFY global survey: Adherence to heart failure guidelines. Eur J Heart Fail. 2016;18:514–22. doi: 10.1002/ejhf.510. [DOI] [PubMed] [Google Scholar]
- 28.Maggioni AP, Anker SD, Dahlström U, Filippatos G, Ponikowski P, Zannad F, et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC heart failure long-term registry. Eur J Heart Fail. 2013;15:1173–84. doi: 10.1093/eurjhf/hft134. [DOI] [PubMed] [Google Scholar]
- 29.Rao VN, Murray E, Butler J, Cooper LB, Cox ZL, Fiuzat M, et al. In-hospital initiation of sodium-glucose cotransporter-2 inhibitors for heart failure with reduced ejection fraction. J Am Coll Cardiol. 2021;78:2004–12. doi: 10.1016/j.jacc.2021.08.064. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Zaman S, Zaman SS, Scholtes T, Shun-Shin MJ, Plymen CM, Francis DP, et al. The mortality risk of deferring optimal medical therapy in heart failure: A systematic comparison against norms for surgical consent and patient information leaflets. Eur J Heart Fail. 2017;19:1401–9. doi: 10.1002/ejhf.838. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Diamond J, DeVore AD. New strategies to prevent rehospitalizations for heart failure. Curr Treat Options Cardiovasc Med. 2022;24:199–212. doi: 10.1007/s11936-022-00969-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Ostrominski JW, Vaduganathan M. Evolving therapeutic strategies for patients hospitalized with new or worsening heart failure across the spectrum of left ventricular ejection fraction. Clin Cardiol. 2022;45(Suppl 1):S40–51. doi: 10.1002/clc.23849. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Rosano GM, Vitale C, Adamo M, Metra M. Roadmap for the management of heart failure patients during the vulnerable phase after heart failure hospitalizations: How to implement excellence in clinical practice. J Cardiovasc Med (Hagerstown) 2022;23:149–56. doi: 10.2459/JCM.0000000000001221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Mebazaa A, Yilmaz MB, Levy P, Ponikowski P, Peacock WF, Laribi S, et al. Recommendations on pre-hospital and early hospital management of acute heart failure: A consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine. Eur J Heart Fail. 2015;17:544–58. doi: 10.1002/ejhf.289. [DOI] [PubMed] [Google Scholar]
- 35.Sulaiman K, Panduranga P, Al-Zakwani I, Alsheikh-Ali AA, AlHabib KF, Al-Suwaidi J, et al. Clinical characteristics, management, and outcomes of acute heart failure patients: Observations from the Gulf acute heart failure registry (Gulf CARE) Eur J Heart Fail. 2015;17:374–84. doi: 10.1002/ejhf.245. [DOI] [PubMed] [Google Scholar]
- 36.Sulaiman KJ, Panduranga P, Al-Zakwani I, Alsheikh-Ali A, Al-Habib K, Al-Suwaidi J, et al. Rationale, design, methodology and hospital characteristics of the first Gulf acute heart failure registry (Gulf CARE) Heart Views. 2014;15:6–12. doi: 10.4103/1995-705X.132137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The task force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM) Eur J Heart Fail. 2008;10:933–89. doi: 10.1016/j.ejheart.2008.08.005. [DOI] [PubMed] [Google Scholar]
- 38.Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to update the 2001 guidelines for the evaluation and management of heart failure): Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation. 2005;112:e154–235. doi: 10.1161/CIRCULATIONAHA.105.167586. [DOI] [PubMed] [Google Scholar]
- 39.McDonald M, Virani S, Chan M, Ducharme A, Ezekowitz JA, Giannetti N, et al. CCS/CHFS heart failure guidelines update: Defining a new pharmacologic standard of care for heart failure with reduced ejection fraction. Can J Cardiol. 2021;37:531–46. doi: 10.1016/j.cjca.2021.01.017. [DOI] [PubMed] [Google Scholar]
- 40.Wirtz HS, Sheer R, Honarpour N, Casebeer AW, Simmons JD, Kurtz CE, et al. Real-world analysis of guideline-based therapy after hospitalization for heart failure. J Am Heart Assoc. 2020;9:e015042. doi: 10.1161/JAHA.119.015042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Carroll R, Mudge A, Suna J, Denaro C, Atherton J. Prescribing and up-titration in recently hospitalized heart failure patients attending a disease management program. Int J Cardiol. 2016;216:121–7. doi: 10.1016/j.ijcard.2016.04.084. [DOI] [PubMed] [Google Scholar]
- 42.Kim KA, Kim ES, Youn JC, Lee HS, Jeon S, Lee HY, et al. A dose-response relationship of renin-angiotensin system blockers and beta-blockers in patients with acute heart failure syndrome: A nationwide prospective cohort study. Eur Heart J Cardiovasc Pharmacother. 2022;8:587–99. doi: 10.1093/ehjcvp/pvac002. [DOI] [PubMed] [Google Scholar]
- 43.Ahn MS, Yoo BS, Yoon J, Lee SH, Kim JY, Ahn SG, et al. Prognostic effect of guideline-directed therapy is more noticeable early in the course of heart failure. J Korean Med Sci. 2019;34:e133. doi: 10.3346/jkms.2019.34.e133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Grewal D, Partow-Navid R, Garcia D, Coney J, Fraser G, Stoletniy L, et al. Role of guideline directed medical therapy doses and optimization in patients hospitalized with decompensated systolic heart failure. Am J Cardiol. 2021;151:64–9. doi: 10.1016/j.amjcard.2021.04.017. [DOI] [PubMed] [Google Scholar]
- 45.AlJarallah M, Rajan R, Heshmat H, AlZakwani I, Dashti R, Bulbanat B, et al. Comparison of demographics and outcomes of acute heart failure patients with reduced, midrange and preserved ejection fraction. Ann Clin Cardiol. 2020;2:86–94. [Google Scholar]
- 46.Hanbali DA, Hashmi KA, Za’abi MA, Al-Zakwani I. Evaluation of guideline-based cardiovascular medications and their respective doses in heart failure patients in Oman. Int J Clin Pharm. 2021;43:878–83. doi: 10.1007/s11096-020-01190-2. [DOI] [PubMed] [Google Scholar]
- 47.Alem MM. Clinical, echocardiographic, and therapeutic characteristics of heart failure in patients with preserved, mid-range, and reduced ejection fraction: Future directions. Int J Gen Med. 2021;14:459–67. doi: 10.2147/IJGM.S288733. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Lyu S, Yu L, Tan H, Liu S, Liu X, Guo X, et al. Clinical characteristics and prognosis of heart failure with mid-range ejection fraction: Insights from a multi-centre registry study in China. BMC Cardiovasc Disord. 2019;19:209. doi: 10.1186/s12872-019-1177-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Ito M, Wada H, Sakakura K, Ibe T, Ugata Y, Fujita H, et al. Clinical characteristics and long-term outcomes of patients with acute decompensated heart failure with mid-range ejection fraction. Int Heart J. 2019;60:862–9. doi: 10.1536/ihj.18-631. [DOI] [PubMed] [Google Scholar]
- 50.Yaku H, Ozasa N, Morimoto T, Inuzuka Y, Tamaki Y, Yamamoto E, et al. Demographics, management, and in-hospital outcome of hospitalized acute heart failure syndrome patients in contemporary real clinical practice in Japan – Observations from the prospective, multicenter Kyoto Congestive Heart Failure (KCHF) registry. Circ J. 2018;82:2811–9. doi: 10.1253/circj.CJ-17-1386. [DOI] [PubMed] [Google Scholar]
- 51.Shiga T, Suzuki A, Haruta S, Mori F, Ota Y, Yagi M, et al. Clinical characteristics of hospitalized heart failure patients with preserved, mid-range, and reduced ejection fractions in Japan. ESC Heart Fail. 2019;6:475–86. doi: 10.1002/ehf2.12418. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Guisado-Espartero ME, Salamanca-Bautista P, Aramburu-Bodas Ó, Conde-Martel A, Arias-Jiménez JL, Llàcer-Iborra P, et al. Heart failure with mid-range ejection fraction in patients admitted to internal medicine departments: Findings from the RICA registry. Int J Cardiol. 2018;255:124–8. doi: 10.1016/j.ijcard.2017.07.101. [DOI] [PubMed] [Google Scholar]
- 53.Jan RK, Alsheikh-Ali A, Mulla AA, Sulaiman K, Panduranga P, Al-Mahmeed W, et al. Outcomes of guideline-based medical therapy in patients with acute heart failure and reduced left ventricular ejection fraction: Observations from the Gulf acute heart failure registry (Gulf CARE) Medicine (Baltimore) 2022;101:e29452. doi: 10.1097/MD.0000000000029452. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Zubaid M, Rashed W, Ridha M, Bazargani N, Hamad A, Banna RA, et al. Implementation of guideline-recommended therapies for patients with heart failure and reduced ejection fraction: A regional Arab Middle East experience. Angiology. 2020;71:431–7. doi: 10.1177/0003319720905742. [DOI] [PubMed] [Google Scholar]
- 55.Greene SJ, Tan X, Yeh YC, Bernauer M, Zaidi O, Yang M, et al. Factors associated with non-use and sub-target dosing of medical therapy for heart failure with reduced ejection fraction. Heart Fail Rev. 2022;27:741–53. doi: 10.1007/s10741-021-10077-x. [DOI] [PubMed] [Google Scholar]
- 56.Swat SA, Xu H, Allen LA, Greene SJ, DeVore AD, Matsouaka RA, et al. Opportunities and achievement of medication initiation among inpatients with heart failure with reduced ejection fraction. JACC Heart Fail. 2023;11:918–29. doi: 10.1016/j.jchf.2023.04.015. [DOI] [PubMed] [Google Scholar]
- 57.Mentz RJ, Lautsch D, Pulungan Z, Kim S, Hilkert R, Teigland C, et al. Medication trajectory and treatment patterns in Medicare patients with heart failure and reduced ejection fraction. J Card Fail. 2022;28:1349–54. doi: 10.1016/j.cardfail.2021.11.013. [DOI] [PubMed] [Google Scholar]
- 58.Rosano GM, Allen LA, Abdin A, Lindenfeld J, O’Meara E, Lam CS, et al. Drug layering in heart failure: Phenotype-guided initiation. JACC Heart Fail. 2021;9:775–83. doi: 10.1016/j.jchf.2021.06.011. [DOI] [PubMed] [Google Scholar]
- 59.Komajda M, Böhm M, Borer JS, Ford I, Tavazzi L, Pannaux M, et al. Incremental benefit of drug therapies for chronic heart failure with reduced ejection fraction: A network meta-analysis. Eur J Heart Fail. 2018;20:1315–22. doi: 10.1002/ejhf.1234. [DOI] [PubMed] [Google Scholar]
- 60.Burnett H, Earley A, Voors AA, Senni M, McMurray JJ, Deschaseaux C, et al. Thirty years of evidence on the efficacy of drug treatments for chronic heart failure with reduced ejection fraction: A network meta-analysis. Circ Heart Fail. 2017;10:e003529. doi: 10.1161/CIRCHEARTFAILURE.116.003529. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Jarjour M, Leclerc J, Bouabdallaoui N, Ahnadi C, Brouillette D, de Denus S, et al. Optimization of pharmacotherapies for ambulatory patients with heart failure and reduced ejection fraction is associated with improved outcomes. Int J Cardiol. 2023;370:300–8. doi: 10.1016/j.ijcard.2022.09.058. [DOI] [PubMed] [Google Scholar]
- 62.Pierce JB, Mentz RJ, Sun JL, Alhanti B, Whellan DJ, Kraus WE, et al. Titration of medical therapy and clinical outcomes among patients with heart failure with reduced ejection fraction: Findings from the HF-ACTION trial. Am Heart J. 2022;251:115–26. doi: 10.1016/j.ahj.2022.05.018. [DOI] [PubMed] [Google Scholar]
- 63.Greene SJ, Butler J, Hellkamp AS, Spertus JA, Vaduganathan M, Devore AD, et al. Comparative effectiveness of dosing of medical therapy for heart failure: From the CHAMP-HF registry. J Card Fail. 2022;28:370–84. doi: 10.1016/j.cardfail.2021.08.023. [DOI] [PubMed] [Google Scholar]
- 64.Bak M, Choi JO. Optimization of guideline-directed medical treatment for heart failure patients with reduced ejection fraction. Korean J Intern Med. 2023;38:595–606. doi: 10.3904/kjim.2023.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Kim SE, Yoo BS. Treatment strategies of improving quality of care in patients with heart failure. Korean Circ J. 2023;53:294–312. doi: 10.4070/kcj.2023.0024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Teng TK, Tromp J, Tay WT, Anand I, Ouwerkerk W, Chopra V, et al. Prescribing patterns of evidence-based heart failure pharmacotherapy and outcomes in the ASIAN-HF registry: A cohort study. Lancet Glob Health. 2018;6:e1008–18. doi: 10.1016/S2214-109X(18)30306-1. [DOI] [PubMed] [Google Scholar]
- 67.Ouwerkerk W, Voors AA, Anker SD, Cleland JG, Dickstein K, Filippatos G, et al. Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: A prospective European study. Eur Heart J. 2017;38:1883–90. doi: 10.1093/eurheartj/ehx026. [DOI] [PubMed] [Google Scholar]
- 68.Greene SJ, Fonarow GC. Clinical inertia and medical therapy for heart failure: The unintended harms of ‘first, do no harm’. Eur J Heart Fail. 2021;23:1343–5. doi: 10.1002/ejhf.2283. [DOI] [PubMed] [Google Scholar]
- 69.Girerd N, Von Hunolstein JJ, Pellicori P, Bayés-Genís A, Jaarsma T, Lund LH, et al. Therapeutic inertia in the pharmacological management of heart failure with reduced ejection fraction. ESC Heart Fail. 2022;9:2063–9. doi: 10.1002/ehf2.13929. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Butler J, Yang M, Sawhney B, Chakladar S, Yang L, Djatche LM. Treatment patterns and clinical outcomes among patients<65 years with a worsening heart failure event. Eur J Heart Fail. 2021;23:1334–42. doi: 10.1002/ejhf.2252. [DOI] [PubMed] [Google Scholar]
- 71.Al-Aghbari S, Al-Maqbali JS, Alawi AM, Za’abi MA, Al-Zakwani I. Guideline-directed medical therapy in heart failure patients with reduced ejection fraction in Oman: Utilization, reasons behind non-prescribing, and dose optimization. Pharm Pract (Granada) 2022;20:2642. doi: 10.18549/PharmPract.2022.2.2642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Jarjour M, Henri C, de Denus S, Fortier A, Bouabdallaoui N, Nigam A, et al. Care gaps in adherence to heart failure guidelines: Clinical inertia or physiological limitations? JACC Heart Fail. 2020;8:725–38. doi: 10.1016/j.jchf.2020.04.019. [DOI] [PubMed] [Google Scholar]
