|Year : 2020 | Volume
| Issue : 2 | Page : 86-94
Comparison of demographics and outcomes of acute heart failure patients with reduced, mid-range, and preserved ejection fraction
, Rajesh Rajan1
, Hussein Heshmat2, Ibrahim Al-Zakwani3
, Raja Dashti1
, Bassam Bulbanat1, Mustafa Ridha4, Kadhim Sulaiman5, Alawi A Alsheikh-Ali6, Prashanth Panduranga7, Khalid F AlHabib8, Jassim Al Suwaidi9, Wael Al-Mahmeed10, Hussam AlFaleh8, Abdelfatah Elasfar11, Ahmed Al-Motarreb12, Nooshin Bazargani13, Nidal Asaad14, Haitham Amin15
1 Department of Cardiology, Sabah Al Ahmed Cardiac Centre, Kuwait City, Kuwait
2 Department of Cardiology, Kasr Al Ainy Medical School, Cairo University, Cairo, Egypt
3 Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
4 Division of Cardiology, Al-Dabous Cardiac Centre, Al Adan Hospital, Kuwait City, Kuwait
5 Department of Cardiology, Royal Hospital, and Director General of Specialized Medical Care, Ministry of Health, Muscat, Oman
6 Department of Cardiology, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
7 Department of Cardiology, Royal Hospital, Muscat, Oman
8 Department of Cardiac Sciences, King Fahad Cardiac Centre, King Saud University, Riyadh, Saudi Arabia
9 Department of Adult Cardiology, Hamad Medical Corporation and Qatar Cardiovascular Research Centre, Doha, Qatar
10 SCleveland Clinic, Heart and Vascular Institute, Abu Dhabi, United Arab Emirates
11 Department of Adult Cardiology, King Salman Heart Centre, King Fahad Medical City, Riyadh, Saudi Arabia; Department of Cardiology, Tanta University, Tanta, Egypt
12 Department of Internal Medicine, Faculty of Medicine, Sana'a University, Sana'a, Yemen
13 Department of Cardiology, Dubai Hospital, Dubai, United Arab Emirates
14 Department of Adult Cardiology, Hamad Medical Corporation, Doha, Qatar
15 Mohammed Bin Khalifa Cardiac Centre, Manama, Bahrain
|Date of Submission||20-Aug-2020|
|Date of Decision||16-Sep-2020|
|Date of Acceptance||20-Sep-2020|
|Date of Web Publication||19-Oct-2020|
Dr. Rajesh Rajan
Department of Cardiology, Sabah Al Ahmed Cardiac Centre, Kuwait City 13001
Source of Support: None, Conflict of Interest: None
Background: Heart failure (HF) burden in the developing world is not well quantified. Objectives: The objective is to evaluate the demographics and outcomes of acute HF patients with reduced ejection fraction (EF) (<40%) (HFr EF), HF with midrange EF (40%–49%) (HFmr EF) and HF with preserved EF (≥50%) (HFp EF) in the Arabian Gulf. Methods: Gulf CARE registry analyzed 4577 HF patients admitted to 47 hospitals in seven Middle Eastern countries (Kuwait, Oman, Qatar, Saudi Arabia, United Arab Emirates, Bahrain, and Yemen.) Analyses were performed using multivariate statistical techniques. Results: The overall median age was 60 (50–70) years and 63% (n = 2887) were male. The most prominent comorbidities included hypertension (61%; n = 2783), coronary artery disease (60%; n = 2762), and diabetes mellitus (49%; n = 2258). A total of 59% (n = 2683) of the patients had HFr EF, 21% (n = 962) had HFmr EF and 20% (n = 932) had HFp EF. Compared to those with HFr EF, patients with HFmr EF and HFp EF were more likely to be associated with hypertension (57% vs. 67% vs. 64%; P < 0.001), diabetes mellitus (47% vs. 57% vs. 51%; P = 0.002), and higher systolic blood pressure (133 vs. 143 vs. 143 mmHg; P < 0.001). Multiple logistic regressions demonstrated that there were no significant differences among the groups with regards to the 3-month (overall adjusted P value; P = 0.188) and 12-month (P = 0.220) cumulative all-cause mortality. The results also indicated that there were no significant differences among the groups with regards to the 3-month (P = 0.117) and 12-month (P = 0.244) re-hospitalization rates for HF. Conclusions: No significant differences among the groups with regards to 3-month and 12-month all-cause mortality and re-hospitalization rates for HF were observed between the groups in the Arabian Gulf.
Keywords: Acute heart failure, Middle East, mortality, outcome, re-hospitalization
|How to cite this article:|
Al-Jarallah M, Rajan R, Heshmat H, Al-Zakwani I, Dashti R, Bulbanat B, Ridha M, Sulaiman K, Alsheikh-Ali AA, Panduranga P, AlHabib KF, Al Suwaidi J, Al-Mahmeed W, AlFaleh H, Elasfar A, Al-Motarreb A, Bazargani N, Asaad N, Amin H. Comparison of demographics and outcomes of acute heart failure patients with reduced, mid-range, and preserved ejection fraction. Ann Clin Cardiol 2020;2:86-94
|How to cite this URL:|
Al-Jarallah M, Rajan R, Heshmat H, Al-Zakwani I, Dashti R, Bulbanat B, Ridha M, Sulaiman K, Alsheikh-Ali AA, Panduranga P, AlHabib KF, Al Suwaidi J, Al-Mahmeed W, AlFaleh H, Elasfar A, Al-Motarreb A, Bazargani N, Asaad N, Amin H. Comparison of demographics and outcomes of acute heart failure patients with reduced, mid-range, and preserved ejection fraction. Ann Clin Cardiol [serial online] 2020 [cited 2021 Apr 12];2:86-94. Available from: http://www.onlineacc.org/text.asp?2020/2/2/86/298607
| Introduction|| |
Heart failure (HF) is a growing public health problem with an estimated prevalence of over 37 million people worldwide. Although the magnitude of HF burden in the developing world is not well quantified, enormous growth in the prevalence of HF is expected as the population ages, and the pervasiveness of HF risk factors, such as hypertension, coronary artery disease (CAD), and obesity, increases., Furthermore, it is also postulated that improvements in survival after myocardial infarction (MI) could also have contributed to the increase in HF prevalence due to advances in acute coronary syndrome (ACS) management. It is expected, in the US, that HF prevalence will increase by 25% by the year 2030. Across the globe, 17%–45% of patients admitted to the hospital with HF will die within 1 year of admission and the majority will die within 5 years of admission.,
A substantial proportion of patients with the clinical syndrome of HF has normal or preserved ejection fraction (EF) (≥50%) termed HF with preserved EF (HFp EF)., The prevalence of HFp EF varies from 30% in a US ambulatory cohort of veterans  to 67% in Taiwan. Apart from the HF with reduced EF (<40%) (HFr EF), the recent guidelines by the European Society of Cardiology (ESC) have recognized a third group of HF patients with near-normal (40%–49%) EF. This group was termed HF with midrange EF (HFmr EF). Patients with HFmr EF, most probably, have primarily mild systolic dysfunction, but with features of diastolic dysfunction. It is unclear whether this intermediate form of HF is an early phase of HFr EF or actually, a form of HFp EF enriched with CAD.
The clinical features of patients with HFp EF and prognosis have been described for patients in the Americas, Europe and Asia, but not in the Middle East., Therefore, in this study, we sought to determine the clinical features, prevalence, and prognosis of patients in the Arabian Gulf region using data from a large multinational registry.
| Methods|| |
We retrospectively analyzed patients with HFp EF and HFmr EF as well as those with HFr EF using data collected from the Gulf aCute heArt failuRe rEgistry (CARE). The design of this registry has previously been described  clinicaltrials.gov (NCT01467973). In brief, Gulf CARE is a prospective, multinational, multi-center registry of patients aged ≥ 8 years admitted to hospital with a diagnosis of acute HF (AHF) in seven Middle Eastern Gulf countries: Saudi Arabia, Kuwait, Qatar, Bahrain, Oman, United Arab Emirates, and Yemen. All data were collected prospectively at the point of initial care, throughout hospitalization, and at 3-month and 1-year follow-ups. Follow-ups at 3- and 12-month were done either through a clinic visit or telephonically. Data on length of hospital stay, hospital readmission rates over 3-month and at 1 year, and mortality (in-hospital, at 3-month and at 1 year) were also included. The study recruitment was from February to November 2012.
Definition of heart failure
AHF was defined according to 2008 ESC guidelines  as the rapid onset of symptoms and signs secondary to abnormal cardiac function, including (i) symptoms (dyspnea at rest or on exercise, fatigue, tiredness, and ankle swelling), (ii) signs (tachycardia, tachypnea, elevated jugular venous pressure, pulmonary rales, pleural effusion, hepatomegaly, and peripheral edema), and (iii) objective evidence of structural or functional abnormality of the heart at rest (third heart sound, murmurs, cardiomegaly, abnormal echocardiogram, and raised natriuretic peptide concentration). AHF was further classified as either acute decompensated chronic HF defined as the worsening of HF in patients with a previous diagnosis or hospitalization for HF or new-onset AHF (de novo AHF). De novo AHF was defined as AHF in patients with no prior HF.
HFr EF, HFmr EF, and HFp EF were diagnosed when patients with symptoms and signs of HF had a measured EF of <40%, 40%–49%, and ≥50%, respectively.,,, Patients with HF who were discharged from the emergency room without admission were excluded from the registry. Patients with no available record of EF were also excluded from the analysis.
CAD was diagnosed if any of the following conditions were present: at least one major epicardial coronary artery determined by coronary angiography to have >70% obstruction, history of MI associated with wall motion abnormality on echocardiography or gated blood pool imaging, and/or stress testing (with or without imaging). Hypertension was defined as: history of hypertension diagnosed and treated with a hypertensive medication or blood pressure >140 mm Hg systolic or 90 mm Hg diastolic on at least 2 occasions or blood pressure >130 mm Hg systolic or 80 mm Hg diastolic on at least 2 occasions for patients with diabetes or chronic kidney disease (CKD).
Continuous variables were expressed as means and standard deviation and compared using analysis of variance (ANOVA) with multiple pairwise comparisons performed using Bonferroni test. Skewed continuous variables or those that violated the Bartlett's test for equal variances for ANOVA, were expressed as medians and interquartile ranges and analyzed using Kruskal–Wallis with multiple pairwise comparisons performed using Mann–Whitney–Wilcoxon test. Categorical variables were summarized as frequency and percentages and analyzed using Chi-square test or Fisher's exact tests, as appropriate.
Multivariable analyses were conducted using logistic regression models utilizing the simultaneous method to evaluate the impact of HF (HFr EF, HFmr EF, and HFp EF) on all-cause mortality and rehospitalizations for HF at 3- and at 12-month and adjusted for age, gender, body mass index, smoking, khat chewing, peripheral vascular disease, hypertension, diabetes mellitus, prior stroke/transient ischemic attack, systolic BP, diastolic BP, serum creatinine, in-hospital percutaneous coronary intervention or coronary artery bypass graft, admission diagnosis, New York Heart Association class, in-hospital course (included noninvasive ventilation, intubation/ventilation, cardiogenic shock, inotropes, intra-aortic balloon pump, acute dialysis/ultrafiltration, atrial fibrillation requiring therapy, major bleeding, blood transfusion, stroke, and systemic infection requiring therapy), discharged medications (diuretics, digoxin, oral nitrates, calcium channel blockers, beta blockers, aldosterone antagonist, angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers, aspirin, If channel blocker (ivabradine). A P < 0.05 was considered statistically significant. Statistical analyses were performed using STATA version 13.1 (Stata Corporation, College Station, TX, USA).
| Results|| |
The Gulf CARE registry recruited 5005 patients, however, only 4577 patients were included in this study. The overall median age was 60 (50–70) years, ranging from 18 to 99 years, and 63% (n = 2887) were male. Most patients were cared for by cardiologists (73%; n = 3332) while the rest by internists (27%; n = 1430). A total of 1778 (39%) patients were initially admitted to intensive care, 1321 (29%) to a monitored bed, and 1478 (32%) to a nonmonitored bed. A total of 2783 (61%) patients had hypertension, 2258 (49%) had diabetes mellitus and 1646 (36%) patients had dyslipidemia. Atrial fibrillation was present in 12% (n = 559) of the patients. [Figure 1] shows patient selection flow chart as well as losses to follow-up. At the end of the study, a total of 1.5% (n = 63) of the patients were lost to follow-up.
In the entire cohort, the median EF was 35% (25%–45%). A proportion of patients with HFr EF, HFmr EF, and HFp EF was 59% (n = 2683), 21% (n = 962), and 20% (n = 932), respectively. At hospital dismissal, the etiology of HF was ACS in 1259 (28%) patients, primary cardiomyopathy in 854 (19%) patients, hypertensive heart disease in 697 (15%) patients, primary valve pathology in 441 (9.6%) patients, pulmonary hypertension in 116 (2.5%) patients, and congenital heart disease in 78 (0.4%) patients. The median hospitalization was 7 (4–10) days. All-cause in-hospital mortality of the entire cohort was 5.2% (n = 236).
When compared to patients with HFr EF, patients with HFp EF were more likely to be older and female, have atrial fibrillation, CKD/dialysis, diabetes mellitus, hypertension, sleep apnea requiring therapy, obesity (≥30 kg/m 2), higher waist circumference, higher systolic BP, and higher pulmonary arterial pressure [Table 1] and [Table 2]. Patients with HFmr EF were more likely to be older, female, khat users, have CAD, diabetes mellitus, hypertension, chest pain, obesity (≥30 kg/m 2), higher waist circumference, higher systolic and diastolic BP, elevated troponin and total cholesterol, ACS as a precipitating cause of HF, and lower in-hospital mortality, when compared to those with HFr EF.
|Table 1: Demographic, clinical and presentation characteristics stratified by ejection fraction|
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|Table 2: Physical examination, electrocardiogram, laboratory characteristics and precipitating causes of heart failure, length of hospital stay and in-hospital mortality stratified by ejection fraction|
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At hospital discharge, patients with HFmr EF and HFp EF were less likely to receive diuretics, beta-blockers, ACEIs, and aldosterone antagonists when compared to patients with HFr EF. The utilization of other medications as well as implantable device therapies (including cardiac resynchronization therapy-defibrillator (CRT), CRT-pacemaker, implantable cardioverter defibrillators as well as permanent pacemakers are presented in [Table 3].
|Table 3: Preadmission medications, in-hospital management, and medications at discharge stratified by ejection fraction|
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Multivariate logistic regressions [Table 4] demonstrated that there were no significant differences among the groups with regards to 3-month (overall adjusted P value; P = 0.188) and 12-month (P = 0.220) cumulative all-cause mortality. The results also indicated that there were no significant differences among the groups with regards to 3-month (P = 0.117) and 12-month (P = 0.244) re-hospitalization rates for HF.
|Table 4: Mortality and re-hospitalization rates at 3-month and at 1-year follow-up|
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| Discussion|| |
The Gulf CARE registry is the largest cohort of patients with HF in the Arabian Gulf [Table 5]. The main finding of our study was lower prevalences of both HFmr EF and HFp EF subtypes but a higher prevalence of HFr EF among hospitalized patients with AHF from the Arabian Gulf when compared with patients from other regions [Table 5]. Although each of the three groups of HF presented with very different clinical features, survival of patients in each of the groups at 3-month and at 12-month was not significantly different, and was similar to those reported in other studies. In this registry, there were also no significant differences among HFr EF, HFmr EF, and HFp EF groups with regards to 3-month and 12-month re-hospitalization rates for HF.
|Table 5: Comparison between the Gulf CARE registry and other international heart failure registriesa|
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Clinical characteristics, inpatient interventions, discharge therapies, and mortality rates for patients with HFp EF vary across geographical regions. We observed a 21% prevalence of HFmr EF and 20% prevalence of HFp EF patients among hospitalized patients, a ratio which is smaller than that observed in the other registries,, which has reported a prevalence of HFmr EF and/or HFp EF to be closer to 50%, but similar to that reported in the Japanese registry, which was 22%.
Similar to the current findings, a number of studies have also demonstrated no significant differences in either all-cause mortality or readmissions between the HF groups.,,,, In the Spanish REDINSCOR II study, Gómez-Otero et al., in a prospective observational study, did not observe any differences in total mortality, cause of death, or HF readmission between the groups. Despite a trend toward nonsignificant higher readmission rates in those with HFmr EF when compared to those with HFp EF, Murtaza et al. documented no differences in readmissions and all-cause mortality between the HF groups while Owan et al. showed that survival was slightly better among those with HFp EF when compared to those with HFr EF, however, survival improved in those with HFr EF over time but not in those with HFp EF. Similarly, in their meta-analysis, Altaie and Khalife  reported that there were no significant differences in all-cause hospitalization or re-hospitalization due to HF among HFr EF, HFmr EF, and HFp EF groups. However, Altaie and Khalife did document a lower all-cause death when the HFmr EF group was compared to the HFr EF cohort but no differences were noted between the HFp EF and the HFr EF groups. Bhatia et al. also reported no differences in survival between the HFp EF and the HFr EF groups. As previously reported,,, ACS, specifically STEMIs, were the most common factor precipitating HF in the young Arabian Gulf population.
In line with similar studies,, patients with HFmr EF/HFp EF were older, more likely to be hypertensive than those with HFr EF. The reported prevalence of obstructive and sleep-related breathing disorders in HF ranges from 47% to 81%, attributable to demographic, risk factors, apnea-hypopnea index cut off, and severity of HF in different populations.
 The lower prevalence of sleep apnea observed in our study (2%) could reflect underdiagnosis due to inadequate recognition of this important disorder. The findings suggest that in a “real world” practice in the Arabian Gulf region, sleep apnea might be under-diagnosed in patients with HF.
We found that the prevalence of atrial fibrillation was lower in the Gulf CARE registry than in other registries. This finding could reflect the younger age and lower prevalence of hypertension in our study cohort compared with other cohorts. The significantly higher systolic BP observed among patients with HFmr EF/HFp EF in the present study is also seen in almost all other HFp EF studies., The higher prevalence of hypertension in patients with HFmr EF/HFp EF, and the relationship between uncontrolled BP and left ventricular diastolic dysfunction, underscore the need for aggressive detection and control of systemic hypertension in the general population to prevent the development of HF.
We observed a slower heart rate in patients with HFmr EF/HFp EF than in those with HFr EF. Heart rate differences between patients with HFmr EF/HFp EF and those with HFr EF have not been described in detail in other studies, although the Japanese HF registry, OPTIMIZE-HF  and the National HF Project  also observed slower heart rates in patients with HFp EF. Other studies have observed no heart rate differences between the two (HFmr EF and HFp EF) patient groups. Elevated heart rate is associated with increased cardiovascular-related mortality in patients with HFp EF compared with individuals with HFr EF, although the impact of this factor on all-cause mortality is comparable between the two groups.
Pulmonary hypertension is common in patients with HFp EF and might be related to both postcapillary pulmonary venous hypertension and a reactive precapillary component of pulmonary arterial hypertension. Increased pulmonary artery systolic pressure is associated with higher mortality in patients with HFp EF. We found that pulmonary artery pressure was significantly higher in patients with HFp EF than in those with HFr EF. In clinical practice, significantly increased pulmonary artery pressure in the presence of normal EF should raise the suspicion of HFp EF, especially in the presence of unexplained dyspnea. Notably, though, in the RELAX trial, no improvement in exercise capacity or clinical status was observed with sildenafil treatment in individuals with HFp EF.
The use of cardiovascular evidence-based medications in those with preserved EF was considerably low and may be due to the lack of randomized controlled trials which could demonstrate their benefits in HFp EF. Notably, though, in a large, nationwide registry analysis in patients with HFp EF in the USA published in 2014, the reported use of a beta-blocker was associated with a decrease in all-cause mortality, but not combined all-cause mortality and/or hospitalization, a finding that needs further examination. In our study, patients with HFp EF were also less likely to receive aspirin, clopidogrel, and statins than patients with HFr EF, which is likely to reflect the lower incidence of CAD and ACS in this group.
Interestingly, we observed no differences in survival rates and rates of hospitalization at 12-month in HFp EF and those with HFr EF, and these findings are consistent with those of the most recent registries of HF.,, The incidence of cardiorenal anemia syndrome (CRAS) in the Middle East was reported to be 17% among AHF patients where in HFmr EF/HFp EF CRAS was not associated with increased all-cause mortality.
The main limitation of this study is its retrospective design that may introduce bias through confounding variables not controlled for or measured. Notably, echocardiographic interpretation was at the discretion of the echocardiographer performing the study, and no centralized evaluation was performed. Moreover, diastolic dysfunction data were not collected. The registry did not capture the use of angiotensin receptor-neprilysin inhibitor, which had not yet been approved (approved only in July 2015) at the time of the study. Furthermore, medication adherence after index discharge was not available. Since more than 11% of the patients had missing re-hospitalization information especially at 12-month follow-up, this could have biased the findings significantly. Mortality rates at follow-up were only recorded at 3-month and at 1-year without the exact date of death for each of the patients, and hence, Kaplan–Meier survival curves and the gold standard “Cox proportional hazard regression” could not be performed. Multiple logistic regression models were, therefore, used. Finally, repeat echocardiogram results to see if HFp EF or HFmr EF patients have not deteriorated were not available.
| Conclusions|| |
In this large cohort of hospitalized patients with AHF in the Arabian Gulf region, HFmr EF/HFp EF was less common than HFr EF. Although each of the three subtypes of HF was associated with different clinical features, 3-month and 12-month all-cause mortality rates were similar across the various HF types. The HFp EF cohort was associated with lower 3-month re-hospitalization while the HFmr EF group had higher 12-month re-hospitalization for HF when compared to the HFr EF cohort. These conclusions imply a need for further study in the region.
Gulf CARE is an investigator-initiated study conducted under the auspices of the Gulf Heart Association and funded by Servier, Paris, France; and (for centers in Saudi Arabia) by the Saudi Heart Association.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]