|Year : 2020 | Volume
| Issue : 1 | Page : 29-35
Impact of digoxin on all-cause mortality and re-hospitalizations in acute heart failure patients
Mohammed Al-Jarallah1, Rajesh Rajan1
, Ibrahim Al-Zakwani2, Raja Dashti1, Bassam Bulbanat1, Mustafa Ridha3, Kadhim Sulaiman4, Alawi A Alsheikh-Ali5, Prashanth Panduranga6, Khalid F AlHabib7, Jassim Al Suwaidi8, Wael Al-Mahmeed9, Hussam AlFaleh7, Abdelfatah Elasfar10, Ahmed Al-Motarreb11, Nooshin Bazargani12, Nidal Asaad13, Haitham Amin14
1 Department of Cardiology, Sabah Al Ahmed Cardiac Centre, Kuwait City, Kuwait
2 Department of Pharmacology & Clinical Pharmacy, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman & Gulf Health Research, Muscat, Oman
3 Division of Cardiology, Al-Dabous Cardiac Centre, Al Adan Hospital, Kuwait City, Kuwait
4 Department of Cardiology, Royal Hospital, and Director General of Specialized Medical Care, Ministry of Health, Muscat, Oman
5 College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
6 Department of Cardiology, Royal Hospital, Muscat, Oman
7 Department of Cardiac Sciences, King Fahad Cardiac Centre, King Saud University, Riyadh, Saudi Arabia
8 Department of Adult Cardiology, Hamad Medical Corporation and Qatar Cardiovascular Research Centre, Doha, Qatar
9 Heart and Vascular Institute, Cleveland Clinic, Abu Dhabi, United Arab Emirates
10 Department of Adult Cardiology, King Salman Heart Centre, King Fahad Medical City, Riyadh, Saudi Arabia; Cardiology Department, Tanta University, Tanta, Egypt
11 Department of Internal Medicine, Faculty of Medicine, Sana'a University, Sana'a, Yemen
12 Department of Cardiology, Dubai Hospital, Dubai, United Arab Emirates
13 Department of Adult Cardiology, Hamad Medical Corporation, Doha, Qatar
14 Mohammed Bin Khalifa Cardiac Centre, Manama, Bahrain
|Date of Submission||29-Apr-2020|
|Date of Acceptance||02-May-2020|
|Date of Web Publication||16-Jun-2020|
Dr. Rajesh Rajan
Department of Cardiology, Sabah Al-Ahmad Cardiac Centre, Kuwait City
Source of Support: None, Conflict of Interest: None
Background and Objectives: The use of digoxin in acute heart failure (AHF) is not without controversy. The aim of this study was to examine the impact of digoxin therapy on all-cause mortality and re-hospitalizations for heart failure (HF) at 3 months and 12 months in AHF patients in the Arabian Gulf stratified by left ventricular ejection fraction (EF). Methods: Data were analyzed from 4577 consecutive patients admitted to 47 hospitals in seven Middle Eastern countries with AHF from February to November, 2012. Analyses were performed using univariate and multivariate statistical techniques. Results: The overall mean age of the cohort was 59 ± 15 years, and 63% (n = 2887) were males. At hospital discharge, digoxin was prescribed to 25% (n = 1156) of the patients. Nearly 59% (n = 2683) of the patients had HF with reduced EF (HFr EF) (<40%), 21% (n = 962) had HF with mid-range EF (HFmr EF) (40%–49%), and 20% (n = 932) had HF with preserved EF (HFp EF) (≥50%). The most prominent comorbidities included hypertension (61%; n = 2783), coronary artery disease (60%; n = 2762), and diabetes mellitus (49%; n = 2258). Multivariate logistic regression analysis demonstrated that digoxin use was associated with lower cumulative all-cause mortality at 3-month (adjusted odds ratio [aOR]: 0.57; 95% confidence interval [CI]: 0.41–0.79; P = 0.001) and at 12-month (aOR: 0.74; 95% CI: 0.58–0.96; P = 0.021) follow-up post hospital discharge in patients with HFr EF. There was, however, no survival advantage conferred by digoxin use in those with HFmr EF or HFp EF, at either the 3-month or 12-month follow-up (all P > 0.05). Digoxin use was also not associated with any benefits regarding re-hospitalization for HF at either 3 months or at 12 months in any type of HF (all P > 0.05). Conclusions: Digoxin was associated with lower cumulative all-cause mortality at both 3-month and 12-month follow-ups in AHF patients with reduced EF in the Arabian Gulf. However, digoxin use did not offer any survival advantages in those with HFmr EF and HFp EF after either 3 months or 12 months. Digoxin use was also not associated with any benefits toward re-hospitalizations for HF at a 3-month or 12-month follow-up in AHF patients.
Keywords: Arabian Gulf, digoxin, heart failure, left ventricular ejection fraction, mortality, patient readmission
|How to cite this article:|
Al-Jarallah M, Rajan R, 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. Impact of digoxin on all-cause mortality and re-hospitalizations in acute heart failure patients. Ann Clin Cardiol 2020;2:29-35
|How to cite this URL:|
Al-Jarallah M, Rajan R, 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. Impact of digoxin on all-cause mortality and re-hospitalizations in acute heart failure patients. Ann Clin Cardiol [serial online] 2020 [cited 2020 Jul 3];2:29-35. Available from: http://www.onlineacc.org/text.asp?2020/2/1/29/286470
| Introduction|| |
Digoxin was first described by a Scottish physician Dr. William Withering in 1785 and is a well-established medication with proven benefits in heart failure (HF) patients with reduced ejection fraction (EF) (HFr EF), in terms of decreasing pulmonary capillary wedge pressure and improving cardiac output without influencing heart rate and blood pressure (BP). In the modern era of HF, treatment has improved dramatically, but the role of digoxin remains and is recommended by both American and European guidelines.
In the early 1980s, a few small studies demonstrated the benefits of digoxin in HF patients with sinus rhythm. Many studies have shown the effects of digoxin in improving functional class and symptoms. However, the Digitalis Investigation Group (DIG) study failed to show any beneficial effects of digoxin on overall mortality, but did find an association with relative reductions in readmissions for HF. The majority of the recent studies are against the use of digoxin in HF patients as it is associated with mortality. The aim of this study was to evaluate the role of digoxin in all types of HF (HFr EF, HF with mid-range EF (40%–49%) [HFmr EF], and HF with preserved EF [HFp EF]) in terms of mortality and re-hospitalization rates, which so far have not yet been well explored in the Arabian Gulf region.
| Methods|| |
Gulf CARE is a prospective, multinational, multicenter registry of patients admitted with the diagnosis of acute heart failure (AHF) to 47 hospitals in seven Middle Eastern countries (the 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 variables, comorbidities, behavioral risk factors, clinical presentation, investigations including medication history, and in-hospital 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 seven participating countries. The study was registered at https://www.clinicaltrials.gov/ (NCT01467973).
AHF was defined based on the European Society of Cardiology (ESC) criteria. Definitions of data variables in the CRF were based on the 2008 ESC guidelines and the American College of Cardiology clinical data standards. Khat chewing was defined as chewing khat plant/leaves (Catha edulis, containing cathinone, 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/L (or 2 mg/dL) for 3 months.
Categorical variables were presented as frequency and percentages and were analyzed using a Chi-squared test or a Fisher's exact test, as appropriate. Continuous variables were expressed as means with standard deviation and were compared using a Student's t-test.
Multivariate analyses were conducted using multiple logistic regression utilizing step-wise backward elimination method. The main outcome variables were mortality and re-hospitalization (at 3-month and at 12-month follow-up), stratified by left ventricular EF (LVEF) (HFr EF, HFmr EF, and HFp EF). The main predictor variable was digoxin prescription at hospital discharge. The models were adjusted for age, gender, khat use, smoking, alcohol, body mass index, hypertension, diabetes mellitus, prior stroke/transient ischemic attack, CKD/dialysis, heart rate on admission, systolic BP (SBP) and diastolic BP on admission, in-hospital percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG), and discharge medications (beta-blockers, statins, aspirin, clopidogrel, angiotensin-converting enzyme inhibitor [ACEI], angiotensin receptor blocker, and aldosterone antagonist). P < 0.05 was considered statistically significant. Statistical analyses were performed using STATA version 13.1 (Stata Corporation, College Station, TX, USA).
| Results|| |
The analyzed cohort consisted of 4577 patients, after exclusion of 428 patients (8.6%) with missing LVEF data. The overall mean age of the cohort was 59 ± 15 years, of which 63% (n = 2887) were males. Nearly 55% (n = 2530) of the patients presented with acute decompensated HF (ADCHF) with a mean LVEF of 37 ± 14%. Comorbidities were common in this cohort, particularly hypertension (61%; n = 2783), coronary artery disease (CAD) (60%; n = 2762), diabetes mellitus (49%; n = 2258), and dyslipidemia (36%; n = 1646). Other demographic and clinical characteristics are summarized in [Table 1].
|Table 1: Demographic and clinical characteristics of the cohort stratified by digoxin prescribing among patients with acute heart failure|
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Almost 25% (n = 1156) of the AHF patients were prescribed digoxin at hospital discharge. Those discharged on digoxin were younger (55 vs. 61 years; P < 0.001), more likely to be smokers (25% vs. 21%; P = 0.003), more commonly khat users (23% vs. 17%; P < 0.001), and were less likely to be obese (27.7 vs. 28.3 kg/m2; P = 0.013). They were also less likely to be associated with CAD (44% vs. 66%; P < 0.001), hypertension (46% vs. 66%; P < 0.001), diabetes mellitus (37% vs. 54%; P < 0.001), and CKD/dialysis (9.5% vs. 16%; P < 0.001). Clinical presentation indicated that digoxin patients had statistically significantly lower SBP (128 vs. 140 mmHg; P < 0.001) and LVEF (32% vs. 39%; P < 0.001). During admission, these patients were also less frequently associated with in-hospital PCI/CABG (4.8% vs. 8.5; P < 0.001). Those on digoxin were more likely to be associated with ADCHF compared to those that were not prescribed digoxin (65% vs. 52%; P < 0.001). At discharge, digoxin users were frequently associated with higher (IV) functional class on the New York Heart Association (NYHA) (10% vs. 2.8%; P < 0.001).
The majority of the patients were on standard HF therapy. At the time of hospital discharge, those on digoxin were frequently associated with the co-prescription of oral frusemide (98% vs. 93%; P < 0.001), ACEI (65% vs. 61%; P = 0.004), and aldosterone antagonists (69% vs. 36%; P < 0.001), but were less likely to be prescribed beta-blockers (69% vs. 74%; P = 0.002) when compared to those who were not on digoxin. Information regarding other medications as well as those used before and during admission is presented in [Table 2].
|Table 2: Medication utilization of the cohort stratified by digoxin prescribing among patients with acute heart failure|
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As shown in [Table 3], digoxin use was associated with lower cumulative all-cause mortality at 3-month (adjusted odds ratio [aOR]: 0.57; 95% confidence interval [CI]: 0.41–0.79; P = 0.001) and at 12-month (aOR: 0.74; 95% CI: 0.58–0.96; P = 0.021) follow-up post hospital discharge in AHF patients with reduced EF. There was, however, no survival advantage of digoxin use in those with HFmr EF and HFp EF at either 3-month or at 12-month follow-up (all P > 0.05). [Table 4] demonstrates that digoxin use at the time of hospital discharge was not associated with any reductions in re-hospitalization for HF at 3-month or at 12-month follow-up in all the three types of HF (all P > 0.05).
|Table 3: Impact of digoxin prescribing, at hospital discharge and on 3-month and 1-year mortalities stratified by left ventricular ejection fraction|
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|Table 4: Impact of digoxin prescribing, at hospital discharge and on 3-month and 1-year re-hospitalization for heart failure stratified by left ventricular ejection fraction|
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| Discussion|| |
This study is among the first to extensively explore the role of digoxin in AHF patients in the Arabian Gulf. In this cohort, digoxin was associated with lower all-cause mortality at 3-month and 12-month follow-up in AHF patients with reduced EF. However, digoxin use did not confer any survival advantages to those with HFmr EF and HFp EF at either the 3-month or 12-month follow-up. Furthermore, digoxin use was not associated with any benefits toward re-hospitalization rates at either follow-up in all types of HF.
Contrary to the DIG trial, this study did not show any benefits to the rate of re-hospitalization, but showed a reduction in all-cause mortality in HFr EF patients. This is in contrast to many studies that showed increased mortality and advised that digoxin should not be included in HF medications. The 2013 ACCF/AH guidelines still recommend its use, as do the European guidelines of HF released in 2016, which also recommend digoxin use with Class IIb (Level B). In an analysis of 91,379 HF patients from nine studies, digoxin was associated with increased all-cause mortality. A study conducted in the Middle East showed that digoxin use in HF and atrial fibrillation (Afib) patients did not offer any survival benefits, but was associated with higher long-term mortality in Afib patients without HF.
Serum digoxin levels, especially levels above 0.5 ng/ml, have been demonstrated to be associated with a higher mortality rate. However, our current study is limited in the fact that serum digoxin levels were not captured. Many studies that have shown higher mortality rates with digoxin have associated this with its use in severely sick patients. As per guidelines, digoxin can be given when patients are not responding to the available optimal medical treatment for HF. Digoxin use was associated with increased mortality in women; however, this has not been demonstrated in this study (all P values for gender-related analyses were >0.05 for in-hospital, 3-month, and 12-month mortalities [data not shown]).
Patients on digoxin have been reported to have improved renal function. Digoxin is known for its increased survival benefits in HF patients with a cardiothoracic ratio >55%, NYHA III–-IV, and an EF <25%, and has been shown to be associated with a decline in hospitalization rates in those patients with serum digoxin levels between 0.5 and 0.9 ng/ml. Trials such as RADIANCE and PROVED have shown that addition of digoxin to HF medications may show better treatment efficacy and outcomes., International studies have shown that there was a drastic drop in the rate of prescription of digoxin at discharge in patients with HFr EF, from 33.1% in 2005 to 10.7% in 2014. In the Middle East, prescription utilization has also dropped from 36% in discharged Afib and HF patients to the current levels of 25%. In HFp EF patients, digoxin use was associated with a lower mortality rate and lower re-hospitalization rates when compared to HFr EF patients in a 2-year follow-up study. In a retrospective study of patients with severe pulmonary artery pressure and right ventricular dysfunction, digoxin use demonstrated mortality benefits as well as lower rates of re-hospitalization. Digoxin toxicity is not associated with higher mortality or a prolonged hospital stay. The AFFIRM trial demonstrated an increased all-cause mortality in AF patients with or without HF. Use of digoxin should be judiciously considered to improve survival and reduce re-hospitalization rates. A new risk calculator for HFr EF ( https://www.hfriskcalc.in/ ) has been suggested to predict risks for HF patients.,
The limitation of this study is its nature of being a registry, which may have introduced bias through confounding variables not controlled for or measured, such as iron levels or history of chronic anemia. In some countries, only a few hospitals took part in the registry; hence, the results might not be entirely generalizable. Reasons for underuse of medications or procedures were not known in this study. Echocardiographic interpretation was at the discretion of the person performing the study; no centralized evaluation was performed. Patients' renal function at discharge was unknown, and there are no data regarding the frequency of patients with improvement of renal function. Mortality rates at follow-up were only recorded at the 1-year follow-up without the exact date of death of each patient, and so Kaplan–Meier curves could not be constructed. Future studies need to overcome these limitations.
| Conclusions|| |
Digoxin was associated with lower all-cause mortality at 3 months and 12 months in acute HFr EF in the Arabian Gulf. However, digoxin use did not offer any survival advantages in those with HFmr EF and HFp EF, neither at the 3-month nor at the 12-month follow-up. Digoxin use at hospital discharge was also not associated with any benefits toward re-hospitalization for HF at either the 3-month or 12-month follow-up in AHF patients.
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Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4]