|Year : 2021 | Volume
| Issue : 1 | Page : 14-19
The Impact of mineralocorticoid receptor antagonist use on all-cause mortality in acute heart failure patients
, Mohammed Al-Jarallah2
, Rajesh Rajan2
, Kadhim Sulaiman3, Raja Dashti4
, Bassam Bulbanat5, Alawi A Alsheikh-Ali6, Prashanth Panduranga3, Khalid F AlHabib7, Jassim Al Suwaidi8, Wael Al-Mahmeed6, Hussam AlFaleh9, Abdelfatah Elasfar10, Ahmed Al-Motarreb11, Mustafa Ridha12, Nooshin Bazargani13, Nidal Asaad14, Haitham Amin15, Amar M Salam16
1 Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University; Gulf Health Research, Muscat, Oman
2 Department of Cardiology, Sabah Al-Ahmed Cardiac Center, Al-Amiri Hospital, Kuwait City, Kuwait
3 Department of Cardiology, Royal Hospital, Muscat, Oman
4 Department of Cardiologist, Sabah Al-Ahmed Cardiac Center, Kuwait City, Kuwait
5 Department of Cardiology, Sabah Al Ahmed Cardiac Center, Kuwait City, Kuwait
6 Department of Cardiology, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
7 Department of Cardiac Sciences, King Fahad Cardiac Center, King Saud University, Riyadh, Saudi Arabia
8 Department of Cardiology, Hamad General Hospital and Weill Cornell Medical College, Doha, Qatar
9 Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia
10 Department of Adult Cardiology, Prince Salman Heart Center, King Fahad Medical City, Riyadh, Saudi Arabia; Department of Cardiology, Tanta University, Tanta, Egypt
11 Department of Internal Medicine, Faculty of Medicine, Sana'a University, Sana'a, Yemen, Yemen<
12 Department of Cardiology, Adan Hospital, Kuwait City, Kuwait
13 Department of Cardiology, Dubai Hospital, Dubai, United Arab Emirates
14 Department of Cardiology, Hamad General Hospital and Weill Cornell Medical College, New York City, New York, USA
15 Department of Cardiology, Mohammed Bin Khalifa Cardiac Center, Manama, Bahrain
16 Department of Adult Cardiology, Hamad Medical Corporation, Doha, Qatar
|Date of Submission||04-Feb-2021|
|Date of Decision||02-Apr-2021|
|Date of Acceptance||03-Apr-2021|
|Date of Web Publication||24-May-2021|
Dr. Rajesh Rajan
Department of Cardiology, Sabah Al Ahmed Cardiac Centre, Kuwait City 13001
Source of Support: None, Conflict of Interest: None
Background: The impact of mineralocorticoid receptor antagonist (MRA) use in acute heart failure (AHF) patients in the Middle East is not well studied. The objective of this study was to examine the impact of MRA therapy on all-cause mortality in AHF patients in the Middle East stratified by left ventricular ejection fraction. Methods: Data were analyzed from 3792 consecutive patients admitted to 47 hospitals in 7 Middle Eastern countries. Results: The overall mean age was 59 ± 15 years and 62% (n = 2353) were male. At discharge, MRA therapy was prescribed in 34% (n = 1301) of the patients. A total of 54% (n = 2048) of the patients had AHF with reduced ejection fraction (EF) (HFrEF) (<40%), 23% (n = 880) had HF with mid-range EF (HFmrEF) (40%–49%), and 23% (n = 864) had HF with preserved EF (HFpEF) (≥50%). MRA therapy was associated with lower cumulative all-cause 3-month mortality in those with HFrEF (adjusted odds ratio [aOR], 0.55; 95% [confidence interval (CI): 0.37–0.80: P = 0.002), those with HFmrEF (aOR, 0.43; 95% CI: 0.19–0.99: P = 0.047), and in those with HFpEF (aOR, 0.45; 95% CI: 0.22–0.92: P = 0.029) when compared to those that were not on MRA therapy. MRA therapy was also associated with lower cumulative all-cause 12-month mortality in those with HFrEF (aOR, 0.65; 95% CI: 0.49–0.86: P = 0.002) and in those with HFmrEF (0.52; 95% CI: 0.29–0.91: P = 0.021). Conclusion: MRA therapy was associated with lower all-cause mortality at 3 months and at 12 months in AHF patients with reduced and mid-range EF in the Middle East.
Keywords: Arabs, heart failure, Middle East, mineralocorticoid receptor antagonists, mortality
|How to cite this article:|
Al-Zakwani I, Al-Jarallah M, Rajan R, Sulaiman K, Dashti R, Bulbanat B, Alsheikh-Ali AA, Panduranga P, AlHabib KF, Suwaidi JA, Al-Mahmeed W, AlFaleh H, Elasfar A, Al-Motarreb A, Ridha M, Bazargani N, Asaad N, Amin H, Salam AM. The Impact of mineralocorticoid receptor antagonist use on all-cause mortality in acute heart failure patients. Ann Clin Cardiol 2021;3:14-9
|How to cite this URL:|
Al-Zakwani I, Al-Jarallah M, Rajan R, Sulaiman K, Dashti R, Bulbanat B, Alsheikh-Ali AA, Panduranga P, AlHabib KF, Suwaidi JA, Al-Mahmeed W, AlFaleh H, Elasfar A, Al-Motarreb A, Ridha M, Bazargani N, Asaad N, Amin H, Salam AM. The Impact of mineralocorticoid receptor antagonist use on all-cause mortality in acute heart failure patients. Ann Clin Cardiol [serial online] 2021 [cited 2021 Aug 5];3:14-9. Available from: http://www.onlineacc.org/text.asp?2021/3/1/14/316658
| Introduction|| |
Heart failure (HF) is a global pandemic affecting at least 26 million people worldwide and is associated with significant morbidity and mortality with expenditures estimated at $108 billion annually., HF has recently been categorized into three subtypes: HF with reduced ejection fraction (EF) (HFrEF) (<40%), HF with mid-range EF (HFmrEF) (40%–49%), and HF with preserved EF (HFpEF) (>50%). Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs) in combination with valsartan, beta-blockers, and mineralocorticoid receptor antagonists (MRAs) have been shown to reduce morbidity and mortality in HF patients with reduced EF.,,,,,,, Furthermore, the American College of Cardiology Foundation, the American Heart Association as well as the European Society of Cardiology (ESC) HF guidelines also recommend their use in HF patients with reduced EF.,
The pharmacological management in patients with HFmrEF and HFpEF remains a challenge as the use of these evidence based cardiac medications has not yet been clearly established. Furthermore, there is only scant literature, on their benefits in HF patients with mid-range and preserved EF with contradictory findings. Hence, the aim of this study was to evaluate the impact of MRAs on all-cause mortality in acute HF (AHF) patients stratified by left ventricular EF (LVEF) in the Middle East.
| Methods|| |
Gulf CARE is a prospective, multinational, multicenter registry of patients admitted with the diagnosis of AHF to 47 hospitals in 7 Middle Eastern countries (United Arab Emirates, Kuwait, Saudi Arabia, Bahrain, Oman, Qatar, and Yemen). The registry design, methods, and collected clinical variables have already been described elsewhere., Briefly, patients ≥18 years of age admitted (from February 14, 2012 to November 14, 2012) to the participating hospitals with an admission diagnosis of AHF were recruited. Baseline and admission-based variables captured included data on demographic, comorbidities, behavioral risk factors, clinical presentation, investigations, including medication history, and inhospital outcomes. Follow-up for all-cause mortality was carried out telephonically at 3 months and either telephonically or through outpatient clinic visits at 1-year.
Data entry was carried out online using a custom designed electronic case-record form (CRF) at the Gulf CARE website (www.gulfcare.org). Institutional or national ethical committee or review board approvals were obtained in each of the 7 participating countries. The study was registered at www.clinicaltrials. gov (NCT01467973).
AHF was defined based on the ESC criteria. Definitions of data variables in the CRF were based on the ESC and the American College of Cardiology clinical data standards., Khat chewing was defined as chewing khat plant/leaves (cathaedulis containing cathionine, an amphetamine-like stimulant which can cause euphoria, hypertension, myocardial infarction, and dilated cardiomyopathy) within 1 month of the index admission. Chronic kidney disease (CKD) was defined as glomerular filtration rate of <60 mL/min/1.73 m² or serum creatinine levels >177 mmol (or 2 mg/dL) for 3 months.
Categorical variables were presented as frequency and percentages and analyzed using Chi-squared test or Fisher’s exact test, as appropriate. Continuous variables were expressed as means and standard deviation and compared using Student’s t-test.
Multivariate analyses were conducted using logistic regression model utilizing stepwise-backward elimination method. The main outcome variables were mortalities (at inhospital, 3-month, and at 12-month follow-up) and stratified by left ventricular EF (HFrEF, HFmrEF, and HFpEF), while the main predictor variable was aldosterone antgonist prescribing at hospital discharge (for the inhospital mortality, MRA prescribing before admission was used). The models were adjusted for age, gender, body mass index (BMI), smoking, khatt use, coronary artery disease (CAD), diabetes mellitus, hypertension, prior stroke/transient ischemic attack (TIA), CKD or dialysis, systolic blood pressure (SBP), and prior medications (beta-blocker, digoxin statin, aspirin, clopidogrel, ACEI, and ARB) for the inhospital model, while for the 3- and 12-month logistic models, medications at hospital discharge were used. The goodness of fit of the multivariable logistic model was examined using the Hosmer and Lemeshow goodness-of-fit statistic, while the discriminatory power of the logistic model was assessed by the area under the receiver operating characteristics curve also known as C-index. 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 cohort consists of 5005 patients. However, due to missing information not only on MRA post discharge but also on EF values, the final analyzable sample was 3792 patients. The overall mean age of the sample was 59 ± 15 years, of which 62% (n = 2353) were male. A total of 49% (n = 1840) of the patients presented with acute decompensated heart failure with an overall mean LVEF of 38 ± 14%. Comorbid conditions were common, particularly hypertension (n = 2325; 61%), CAD (n = 2298; 61%), and diabetes mellitus (n = 1879; 50%). A total of 54% (n = 2048) of the patients had HFrEF, 23% (n = 880) had HFmrEF, and 23% (n = 864) had HFpEF. The rest of the demographic and clinical characteristics are shown in [Table 1].
|Table 1: Demographic and clinical characteristics of the cohort stratified by mineralocorticoid receptor antagonist prescribing at hospital discharge among patients admitted with acute heart failure|
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A total of 34% (n = 1301) of the AHF patients were prescribed MRAs therapy at hospital discharge. All patients, except 2, were on spironolactone, with 25 mg (81%) as the most prevalent dose strength. Those discharged on MRA were younger (56 vs. 61 years; P < 0.001) with lower BMI (27.5 vs. 28.5 kg/m2; P < 0.001), but more likely to be male (67% vs. 60%; P < 0.001), smokers (32% vs. 20%; P < 0.001), and Khat users (34% vs. 12%; P < 0.001). However, they were less likely to be associated with the presence of CAD (51% vs. 65%; P < 0.001), hypertension (46% vs. 69%; P < 0.001), diabetes mellitus (35% vs. 57%; P < 0.001), peripheral vascular disease (3.4% vs. 4.9%; P = 0.034), stroke/TIA (6.0% vs. 9.4%; P < 0.001), and CKD/dialysis (3.7% vs. 20%; P < 0.001). Clinical presentation indicated that those on MRA therapy had significantly lower SBP (136 vs. 142 mmHg; P < 0.001), serum creatinine (108 vs. 142 mmol/L; P < 0.001), and LVEF (34% vs. 41%; P < 0.001). At discharge, MRA users were more frequently associated with higher (intravenous) classes on New York Heart Association (NYHA) functional classification (15% vs. 0.3%; P < 0.001).
Majority of the patients were on standard HF therapy. At hospital discharge, those on MRA therapy were more frequently associated with the co-administration of oral diuretics (98% vs. 91%; P < 0.001), ACEI/ARB (88% vs, 73%; P < 0.001), and beta-blockers (75% vs. 70%; P < 0.001) when compared to those who were not on MRA therapy. However, MRA therapy patients were less frequently associated with the prescribing of digoxin (29% vs. 43%; P < 0.001), calcium channel blockers (6.7% vs. 22%; P < 0.001), statins (62% vs. 79%; P < 0.001), and aspirin (85% vs. 80%; P < 0.001). Information on other medications as well as those used before and during admission is given in [Table 2].
|Table 2: Medication utilization of the cohort stratified by mineralocorticoid receptor antagonist prescribing at hospital discharge among patients admitted with acute heart failure|
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As shown in [Table 3], MRA therapy use was associated with lower cumulative all-cause 3-month mortality in those with HFrEF (adjusted odds ratio [aOR], 0.55; 95% confidence interval [CI]: 0.37–0.8: P = 0.002), as well as those with HFmrEF (aOR, 0.43; 95% CI: 0.19–0.99: P = 0.047), and in those with HFpEF (aOR, 0.45; 95% CI: 0.22–0.92: P = 0.029) when compared to those that were not on MRA therapy. Furthermore, MRA therapy was also associated with lower cumulative all-cause 12-month mortality in those with HFrEF (aOR, 0.65; 95% CI: 0.49–0.86: P = 0.002) and in those with HFmrEF (0.52; 95% CI: 0.29–0.91: P = 0.021) but not in those with HFpEF (0.68; 95% CI: 0.40–1.15: P = 0.148). There were, however, no survival advantages of MRA therapy use during inhospital stay.
|Table 3: Impact of mineralocorticoid receptor antagonist therapy on all-cause mortality, at inhospital, at 3 months, and at 1 year stratified by left ventricular ejection fraction (n=3792*)|
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| Discussion|| |
This study, being one of only a few studies worldwide, evaluated the impact of MRA therapy on all-cause mortality in AHF patients in the Middle East stratified by LVEF. MRA therapy was associated with lower all-cause mortality at 3 months and at 12 months in AHF patients with reduced and mid-range EF. The benefits of MRA therapy in patients with preserved EF were only observed transiently at 3-month follow-up but not at 12-month follow-up. Furthermore, MRA therapy was not associated with any survival advantages during inhospital stay.
In an analysis of 9 randomised controlled clinical trials that included a total of 69,229 patients with reduced EF or left ventricular dysfunction, renin–angiotensin–aldosterone system blocker use was associated with a 27% (odds ratio, 0.73; 95% CI: 0.51–0.95) reduction in mortality. One of the latest meta-analyses that evaluated the impact of MRA and its combination with ACEIs, ARBs, beta-blockers, and ARNIs showed that the combination of ACEI + MRA+beta-blocker was associated with a 56% reduction in mortality (hazard ratio (HR), 0.44; 95% CI: 0.26–0.66). Furthermore, there was a 63% (HR, 0.37; 95% CI: 0.19–0.65) reduction in all-cause mortality when MRA was introduced in addition to an ANRI and a beta-blocker. The current Gulf CARE study also demonstrated similar findings with an overall cumulative annual all-cause mortality reduction of 35% in patients with HFrEF.
In the current Gulf CARE study, MRA use was not associated with any long-term survival benefits in patients with HFpEF. This finding has also been replicated in various randomized clinical trials. The meta-analysis demonstrated that the use of spironolactone improved left ventricular dysfunction in HFpEF patients; however, there were no effects with regard to all-cause mortality and hospitalization as well as 6-min walk distance. In the TOPCAT study, treatment with spironolactone was also not associated with any reductions in the incidence of the composite score of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of HF.
In another large meta-analysis evaluating the efficacy and safety of spironolactone in HF patients with mid-range and preserved EF consisting of 11 randomized trials (n = 4539), Xiang et al. reported that those with HFmrEF and HFpEF could benefit from spironolactone and were associated with reduced hospitalizations, brain natriuretic peptide, improved NYHA-functional classification, alleviated myocardial fibrosis by decreasing serum procollagen type I C-terminal propeptide, decreased PIIINP levels and increased 6-min walking distance only in HFpEF. However, patients were associated with increased risk of hyperkalemia and gynecomastia.
This study is not without limitations. The fact that this was a subgroup analysis of an observational study, the possibility of unmeasured confounding variables exists. In some countries, only a few hospitals took part in the registry; hence, the results might not be entirely generalizable to the Arabian Gulf region. Compliance was also not validated in the 12-month follow-up period, only assumed. We reported all-cause inhospital, 3-month, and 1-year all-cause mortality where, if available, cardiovascular mortality would have been more appropriate. Furthermore, mortality rates at follow‐up were only recorded at 3 months and at 1-year follow-up without the specification of the exact date of death of each patient, and hence, the Kaplan–Meier curves could not have been performed. Future studies need to overcome these limitations.
| Conclusions|| |
MRA therapy was associated with lower all-cause mortality at 3 months and at 12 months in AHF patients with reduced and mid-range EF in the Middle East. However, MRA therapy was not associated with any survival advantages during inhospital stay. Future studies are warranted to validate our findings.
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]