Feasibility of Short-Term Use of Ivabradine in Critical Ill Patients Who Have Atrial Fibrillation and Tachycardia

Abstract

Background

Ivabradine is approved for heart rate reduction in patients with stable symptomatic heart failure (HF). The United States Food and Drug Administration and Taiwan Central Health Insurance Agency approved the use of ivabradine for patients with chronic stable HF with sinus rhythm, but it has not yet been approved for patients with acute decompensated HF or with atrial fibrillation (AF).

Objectives

To investigate whether short-term ivabradine use is feasible in critically ill patients with AF and rapid ventricular response (RVR).

Methods

This study retrospectively analyzed 23 patients admitted to an intensive care unit with acute HF and AF-RVR who received ivabradine. All patients initially received a slow IV of amiodarone. Other medications for HF were prescribed according to current HF guidelines. The time taken for ivabradine to reduce HR to 80 beats per minute, referred to as "Time to 80," was measured in each patient.

Results

Overall, 69.6 % (16/23) of the patients had New York Heart Association functional class IV HF. In addition, 60.9% (14/23) of the patients required endotracheal intubation and ventilatory support, with more than half receiving vasopressor treatment to manage hypotension. Five patients died during the study period. The surviving patients had a significantly shorter "Time to 80" compared to those who did not survive (p = 0.037).

Conclusions

Adding ivabradine to standard treatment might be feasible for critically ill patients with AF and tachycardia. The finding that surviving patients had a shorter "Time to 80" duration than those who did not survive may have clinical implications. However, further investigations are needed to assess its clinical utility.

Abbreviations

AF, Atrial fibrillation

AF-RVR, Atrial fibrillation with rapid ventricular response

ALT, Alanine aminotransferase

AST, Aspartate aminotransferase

AV, Atrioventricular

BP, Blood pressure

bpm, Beats per minute

CRP, C-reactive protein

CVD, Cardiovascular disease

DM, Diabetes mellitus

eGFR, Estimated glomerular filtration rate

ER, Emergency department

GOT, Glutamic oxaloacetic transaminase

GPT, Glutamic pyruvic transaminase

HF, Heart failure

HR, Heart rate

ICU, Intensive care unit

IV, Intravenous

LAD, Left anterior descending

LV, Left ventricle

LVEF, Left ventricular ejection fraction

NYHA functional classification, New York Heart Association Functional Classification

OPD, Outpatient department

U.S. FDA, United States Food and Drug Administration

BACKGROUND

Ivabradine is a pure heart rate (HR) lowering agent which acts by inhibiting the I(f) current in the sinus node.^1-5 Ivabradine has been approved in HR reduction in patients with stable, symptomatic chronic heart failure (HF) by the United States (U.S.) Food and Drug Administration (FDA) in April, 2015. The FDA website also issued a "Safety Information Statement" which indicated that ivabradine is contraindicated in patients with acute decompensated heart failure or blood pressure < 90/50 mmHg.⁶ Additionally, the Taiwan Central Health Insurance Administration-National Health Insurance Bureau’s payment regulations specify that ivabradine is indicated for use in patients with stable, symptomatic chronic HF [New York Heart Association (NYHA) functional class II-IV], who have a left ventricular ejection fraction (LVEF) of ≤ 35%, who are in sinus rhythm with a resting HR ≥ 75 beats per minute (bpm), and who are either receiving maximally tolerated doses of beta blockers or have a contraindication to beta-blocker use.⁷ In order words, both the U.S. FDA and Taiwan Central Health Insurance Agency approved the use of ivabradine in chronic stable heart failure with sinus rhythm, but not for those with acute decompensated HF or with atrial fibrillation (AF).

Many articles have reported that elevated resting HR is associated with worse outcomes in patients with HF and reduced LVEF.^8-10 Clinical trial data also indicate that HR reduction itself is an important beneficial mechanism to patients with acute myocardial infarction, chronic HF, or stable angina pectoris.¹¹ This study aimed to investigate whether short-term ivabradine use is beneficial to critically ill patients with atrial fibrillation with rapid ventricular response (AF-RVR).

METHODS

Since the indications for using ivabradine from the Taiwan National Health Insurance Bureau’s payment regulations were that it can only be used in patients with stable, symptomatic chronic HF (NYHA functional class II-IV), with a LVEF of ≤ 35%, and who are in sinus rhythm. The administration of ivabradine in other groups is an off-label use, i.e., patients should pay for the use of this medication themselves. This study retrospectively analyzed patients admitted to our intensive care unit (ICU) who were 20 years or older, from August 1, 2016 to May 31, 2023. Any patient who had acute HF with AF-RVR and had ever received ivabradine to control tachycardia was included. Other medications including beta-blockers, nondihydropyridine calcium channel blockers, digoxin, and amiodarone, etc. were recorded. Electrocardiograms, chest X-rays, clinical characteristics including the vital signs, kidney and liver function, LVEF, whether the patients had shock status, had received mechanical ventilatory support, or use of vasopressors were all recorded. The duration between the initiation of ivabradine and the time point that HR dropped to 80 bpm for at least 4 hours or so called "Time to 80", in each patient was also measured.

Treatment protocol

Since we hoped to control tachycardia promptly, all patients received intravenous amiodarone 150 mg slowly for 10 minutes initially. If tachycardia persisted, we gave continuous amiodarone infusion with a rate of 11 mL/hr using a premixed solution. This solution was made by mixing amiodarone 900 mg in 5% glucose 250 mL before infusion. Except amiodarone infusion, we routinely administered beta-blocker if there was no contraindication. Diltiazem might be used if the patient could not use beta-blocker due to contraindications or other causes such as allergy or hypotension. Ivabradine was used as well if HR still more than 100 bpm and without hypotension. If a patient had hypotension, we would give fluid resuscitation and administered vasopressor (norepinephrine usually was the first choice) to stablize blood pressure (BP). Dopamine was also given if clinically indicated. If a patient had low blood pressure, beta-blocker was not used but ivabradine could be used if systolic BP > 115 mmHg. However, if patients needed vasopessor to control hypotension, oral ivabradine (5 mg) twice daily could be given after systolic BP had increased to ≥ 115 mmHg. Ivabradine treatment was continued until patient discharge. Other medications for treating HF were prescribed according to the current consensus document from the Taiwan Society of Cardiology.¹²

Statistical analysis

All statistical analyses were performed using SPSS version 26 (IBM Corp., Armonk, NY, USA). Categorical variables are expressed as count (percentage) and continuous variables as mean ± standard deviation. Differences between survival and non-survival groups were assessed using the Mann-Whitney U test for continuous variables and the Chi-square test for categorical variables. A p value ≤ 0.05 was considered statistically significant.

RESULTS

Sixty-one patients received ivabradine during the study period, of whom 33 had sinus rhythm and 28 had AF. Five of these 28 patients were not included because they had not received intravenous amiodarone in the early stages. The other 23 patients, 14 male and 9 female, aged from 39 to 86 (mean: 71.4 ± 13.8) years who had AF-RVR were enrolled eventually. Since 5 of these patients died, the patients were divided into the survival and non-survival groups. The characteristics and clinical data of these two groups are shown in Table 1. From Table 1, we found that the survival group was significantly younger than the non-survival group (69.5 ± 14.6 vs. 81.6 ± 2.9; p = 0.017). The "Time to 80" was significantly shorter in the survival group compared with the non-survival group (22.7 ± 18.9 vs. 109.6 ± 106.1, p = 0.037). However, there were no differences in other variables between the two groups. Since all of our patients were critically ill cases who had AF-RVR, we first present the brief histories of our experiences in managing these two typical patients, and then described the other results subsequently.

Table 1. Demographic data of two groups.

	Survival (n = 18)	Non-survival (n = 5)	p value
Age (yrs)	69.5 ± 14.6	81.6 ± 2.9	0.017
Sex (M/F)	M = 12, F = 6	M = 2, F = 3	0.343
BUN (mg/dL)	32.9 ± 13.7	37.4 ± 13.3	0.502
Creatinine (mg/dL)	1.83 ± 1.21	1.59 ± 0.83	0.297
eGFR (ml/min/1.73 m2)	58.3 ± 8.4	53.5 ± 37.3	0.941
SGOT (U/L)	121.6 ± 116.6	260.2 ± 527.7	0.290
SGPT (U/L)	36.1 ± 21.0	40.2 ± 33.2	1.000
Total bilirubin (mg/dL)	0.90 ± 0.45	0.80 ± 0.35	0.760
NT-pro-BNP (pg/mL)	10501.1 ± 10977.9	11514.0 ± 13260.6	0.852
Heart rate (beat/min)	129.1 ± 14.7	128.8 ± 13.7	0.852
LVEF (%)	47.9 ± 18.4	55.7 ± 17.2	0.233
Time to 80 (hr)	22.7 ± 18.9	109.6 ± 106.14	0.037
On endo/ventilator use (%)	55.6%	80%	0.611
Amiodarone IV (%)	100%	100%	No.D
Beta-blocker (%)	100%	100%	No.D
Calcium channel blocker (%)#	38.9%	40%	1.000
Digoxin (%)	5.6%	0%	1.000
Vasopressor (%)*	61.1%	80%	0.621
Pneumonia(%)	72.2%	60%	0.621
NYHA-functional class			0.272
II-III (No)	7	0
IV (No)	11	5
AMI (%)	50%	40%	1.000
Hypertension (%)	27.8%	20%	1.000
Type 2 DM (%)	11.1%	20%	0.539
Chronic lung disease (%)	5.6%	20%	0.395

AMI, acute myocardial infarction; BUN, blood urea nitrogen; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; No.D, not done; NT-pro-BNP, N-terminal prohormone of B-type natriuretic peptide; On endo, received endotracheal intubation; SGPT, serum glutamate pyruvate transaminase; Time to 80, the duration from initiation of ivabradine to heart rate dropped to 80 beat per minute for at least 4 hours; %, the percentage of case numbers to the total case numbers of each variable.

* Vasopressor included either dopamine or epinephrine. ^# Calcium channel blocker included either diltiazem or verapamil.

Case presentation I

The patient was a 71-year-old man with past histories of right lung cancer, post lobectomy of the right upper lobe, chemotherapy and radiotherapy 12 years previously, hypertension, paroxysmal AF, chronic kidney disease (stage 4), coronary artery disease – for which he had received balloon angioplasty to the left anterior descending (LAD) coronary artery but without stenting, and old thrombotic stroke history. According to his family, he developed shortness of breath in the evening of August 14, 2017. Since dyspnea became more severe, he was brought to our emergency department next morning. At the emergency department, laboratory data revealed creatine kinase-MB (mass) = 5.5 ng/mL, troponin I = 0.149 ng/mL, N-terminal prohormone of B-type natriuretic peptide ≥ 35000 pg/mL, glutamic oxaloacetic transaminase (GOT) also known as aspartate aminotransferase (AST)/glutamic pyruvic transaminase (GPT) also known as alanine aminotransferase (ALT) = 67/68 U/L, blood urea nitrogen = 41 mg/dL, creatinine = 2.41 mg/dL, estimated glomerular filtration rate (eGFR) = 26.5 ml/min/1.73 m², glucose = 118 mg/dL, white blood cell = 12500/μL, hemoglobin = 13.5 g/dL, hematocrit = 42.4%, and c-reactive protein (CRP) = 6.35 mg/dL. Chest X-ray showed cardiomegaly with centrally distributed air space infiltrations and opacification in both lungs, which consistent with alveolar pulmonary edema (Figure 1A). Due to leukocytosis and increased CRP, pneumonia was also considered. The electrocardiogram revealed AF with tachycardia (HR = 125 bpm), right axis deviation, suspected old anteroseptal myocardial infarction, clockwise rotation, and non-specific ST-T change (Figure 2). The patient suddenly developed loss of consciousness, tachypnea, and shock (BP = 68/56 mmHg), he received endotracheal intubation and mechanical ventilation promptly. He was then admitted to our ICU for further management on August 15, 2017.

Figure 1.

(A) The chest X-ray showed cardiomegaly, cephalization of pulmonary vessels, centrally distributed air space infiltrations and diffuse opacification in both lungs, which suggesting alveolar pulmonary edema. (B) Chest X-ray of the same patient, 8 days after treatment, much improvement of pulmonary edema and mildly decrease in cardiac silhouette was noted.

Figure 2.

Electrocardiogram showed atrial fibrillation with tachycardia, right axis deviation, suspect old anteroseptal myocardial infarction, clockwise rotation, and non-specific ST-T change.

After admission, he received dopamine infusion to control low BP and cefepime to treat pneumonia. Furosemide and spironolactone had been used for inducing diuresis. Amiodarone infusion and ivabradin were administered to control AF with tachycardia. Due to past history of coronary artery disease that had been treated with balloon angioplasty, the dual antiplatelets (aspirin and clopidogrel) were administered. Beta-blocker was not used due to low BP. No anticoagulant was given due to abnormal liver function and he had already used dual antiplatelets. On the 2^nd hospital day (August 16), due to skin rash over whole body, cefepime was changed to piperacillin/tazobactam. An antihistamine was added to control the skin rash. Echocardiography revealed mild dilation of left atrium, moderate mitral and tricuspid regurgitation, mild aortic regurgitation, and preserved left ventricular systolic performance with estimated LVEF = 59%. Patient’s HR decreased gradually after treatment, the "time to 80" was 18 hours. In the afternoon of August 16, his BP improved (142/92 mmHg), and dopamine was discontinued. Bisoprolol was administered. On the 4th hospital day (August 18), we tapered furosemide due to plenty amount or urine (4230 ml). Tachycardia became better, and normal sinus rhythm with HR = 73 bpm was noted. Intravenous amiodarone was discontinued and oral amiodarone 200 mg twice daily was administered. On August 21, the patient felt improvement of dyspnea and his respiratory pattern became better. The endotracheal tube was removed. After our aggressive treatment, his general condition improved gradually. He was transferred to an ordinary ward on August 23. A follow-up chest X-ray showed much improvement (Figure 1B). Cardiac catheterization was performed on August 29, which revealed 1-vessel disease (left main artery: patent; LAD: mid 90% stenosis; left circumflex artery: patent; right coronary artery: patent). Percutaneous coronary intervention with a drug eluting stent in the LAD was successfully deployed. The patient was discharged on August 31 and followed-up at our cardiovascular outpatient department (OPD) regularly and uneventfully till update.

Case presentation II

The patient was a 77-year-old woman who had underlying diseases of diabetes mellitus (DM), hypertension and hyperlipidemia. She was regularly followed-up at our OPD. She suffered from chest pain with dyspnea and palpitation for 1 day. Thus, she was brought to our emergency department (ER) for help on November 24, 2016. At our ER, the initial vital signs were body temperature: 36.8 °C, HR: 144 bpm, respiratory rate: 20/min, BP: 154/60 mmHg. Her consciousness was alert. Laboratory examination showed no elevation of cardiac enzyme or proBNP. Other findings showed GOT/GPT (ALT) = 35/30 U/L, blood urea nitrogen = 18 mg/dL, creatinine = 0.76 mg/dL, eGFR = 73.7 ml/min/1.73 m², and glucose = 118 mg/dL. Chest X-ray showed increased infiltration over bi-lateral lung fields. Electrocardiography showed AF with tachycardia (Figure 3). Verapamil 5 mg was intravenously given twice but did not control the tachycardia. Patient’s dyspnea became more severe gradually, and her consciousness became drowsy and SpO2 was 82% despite use of a non-rebreather mask. Therefore, an endotracheal tube was inserted with ventilatory support, and she was admitted to our ICU for further management. In her record, about 6 months ago, the thallium-201 myocardial perfusion scan did not show any evidence of myocardial ischemia or infarction. Another echocardiogram revealed mild concentric left ventricle (LV) hypertrophy, reversed E/A ratio of mitral flow pattern, and normal LV function with estimated LVEF of 75%. A previous electrocardiogram showed a sinus rhythm which indicated that she had a paroxysmal AF. Ceftriaxone was given for 2 days in order to prevent respiratory infection due to endotracheal intubation. Due to tachycardia (HR = 122 bpm), amiodarone 150 mg was given slowly followed by amiodarone 900 mg added in 5% glucose 250 ml with a rate of 11 mL/hr. Bisoprolol was used to control tachycardia. Due to HF, the dose of bisoprolol was not increased. Ivabradine was also administered in order to control tachycardia. Since she had HF, hypertension, age > 75 years, diabetes, and female sex, the CHA₂DS₂-VAS score was 6 points. Rivaroxaban was also prescribed. Other medications included furosemide to induce diuresis, valsartan to control hypertension, and quetiapine before sleep to control insomnia and delirium. Meanwhile, regular insulin was also given to control hyperglycemia according to the sliding scale method. On the 2^nd admission day, Rocephin was shifted to ampicillin and sulbactam due to urine culture found the growth of Escherichia coli. After our aggressive treatment, patient’s HR decreased gradually, the "time to 80" was 24 hours. Her vital signs were: HR: 74-80/min, breaths: 22/min, BP: 139/81 mmHg. Intake/output was: 2036 mL/1770 mL (urine: 1770 mL). Intravenous amiodarone was changed to 1 tablet twice daily. Other medications were the same. On the 3^rd hospital day, vital signs were HR: 63-72 beats/min, RR: 18/min, BP: 145/65 mmHg, and intake/output: 1972 mL/1420 mL (urine: 1420 mL). Oral amiodarone was changed to 1 tab daily, other medications were the same. Weaning training was started. After two more days weaning training, her general condition improved: HR: 52/min, breath: 15/min, BP: 102/52 mmHg, and intake/output: 1574 mL/1190 ml (urine: 1190 ml). Electrocardiogram showed sinus bradycardia with HR of 52 bpm and non-specific ST-T change (Figure 4). Patient was successfully extubated. Due to bradycardia (HR: 48-52 bpm), ivabradine was changed to 0.5 tablet twice daily.

Figure 3.

Electrocardiogram showed atrial fibrillation with tachycardia and non-specific ST-T change.

Figure 4.

Electrocardiogram showed sinus bradycardia with non-specific ST-T change.

Other results

In this study, 69.6% (16/23) of our patients had a NYHA function class IV HF, 17.4% (4/23) and 13.0% (3/23) had a functional class III and II heart failure, respectively. Most patients (95.7%) received beta-blocker treatment, but one patient did not receive beta-blocker due to asthma history; this patient received a calcium blocker (Diltiazem) to control tachycardia.

In addition, 60.9% (14/23) of the patients underwent endotracheal intubation and ventilatory support. More than half of the study patients needed vasopressor treatment to control of their hypotension, and norepinephrine and dopamine were used in 14 (60.9%) and 10 (43.5%) of them, respectively. These data indicated that the enrolled cases were quite critically ill at the time of admission. As for other comorbidities, acute myocardial infarction presented in nine patients, hypertension in five, diabetes mellitus in two, and chronic lung disease in two.

Ivabradine was given to all patients with tachycardia. No side effects were noted after ivabradine use including changes in BP, gastrointestinal upset, drowsiness, or mentality change. Of the study patients, five (21.7%) died in the hospital. The cause of death was refractory failure in three patients, terminal breast cancer in one, and pneumonia with septic shock in another one. For the three patients with refractory heart failure, one had acute myocardial infarction with cardiogenic chock, one had associated acute renal failure, and one had severe aortic regurgitation. The "Time to 80" in these 5 cases was 15 to 264 (mean: 109.6 ± 102.1) hours compared to 2 to 79 (mean: 22.7 ± 18.0) hours in the survivors. The surviving patients had a significantly shorter "Time to 80" compared to those who did not survive (p = 0.037) (Figure 5).

Figure 5.

Bar graph of the duration of “Time to 80 (hrs)” between surviving and deceased patients.

DISCUSSION

This study found that the administration of ivabradine to our critically ill patients with AF-RVR had an additive effect in decreasing the patient’s HR without adverse effects even in those with functional class IV HF. To the best of our knowledge, this report might be the first study to use ivabradine in managing critically ill patients with AF-RVR, of whom about 70% had functional class IV HF. About 60.9% of the patients underwent endotracheal intubation and received ventilatory support. More than half of these patients had hypotension that needed vasopressor treatment. Additionally, we found that the "Time to 80" was significantly shorter in the surviving patients compared to those who did not survive. HR reduction has been shown to improve clinical outcome.^8-11 In this study, the "Time to 80" was defined as the duration it took for a rapid heart rate to drop to below 80 bpm. Theoretically, a shorter "Time to 80" indicated rapid control of tachycardia, which suggested a relatively better outcome. Therefore, we believe that the "Time to 80" might be a useful clinical indicator for poor prognosis in critically ill patients with AF-RVR.

This study also showed that the survival group was relatively younger than the non-survival group (p = 0.017). Advanced age may cause changes in physiology and organ functions,¹³ which may subsequently account for the increase in mortality of many diseases. For example, the incidence of cardiovascular disease (CVD) increases with age, and the burden of CVD in the elderly is directly related to the increased mortality and morbidity.¹⁴ It has also found that mortality rates increased with age in patients with pneumonia.¹⁵ In addition, the incidence of sepsis increases with age, especially in those older than 80 years, and is associated with extremely high mortality rates.¹⁶ Furthermore, age has been reported to be an independent predictor of death in old patients with acute kidney injury.¹⁷ It is also true for DM patient, that old age DM patients had a relatively higher mortality rate than that of young age.¹⁸ Our finding that the non-survivors were significantly elder than the survivors was consistent with previous reports.^13-18 Nevertheless, the aim of our retrospective analysis was to assess the short-term effect of ivabradine treatment on HR reduction, and the difference in age between the two groups was an incidental finding.

A previous report indicated that a HR-control strategy could reduce adverse drug effects and decrease hospitalizations compared with a rhythm-control strategy in AF patients, although there was no difference in mortality.¹⁹ HR control is usually achieved by using drugs which prolong atrioventricular (AV) node refractoriness such as beta-blockers, nondihydropyridine calcium channel blockers (such as diltiazem or verapamil), and digoxin. However, these medications have their own limitations. For example, diltiazem and verapamil may have negative inotropic effects in patients with reduced LVEF, and beta-blockers may exacerbate conditions such as asthma or depression, and must be used with caution in patients with hypotension. Digoxin is restricted in patients with renal failure, old age, and hypokalemia. Combining beta-blockers and non-dihydropyridine calcium channel blockers can significantly increase the risk of bradycardia and hypotension. In contrast, ivabradine has different mechanisms of decreasing HR. Its effect of inhibiting the I(f) current in the sinus node^20,21 and AV node^22,23 is especially useful in control of tachycardia but without the above side effects. This is why we chose ivabradine in this study.

According to the AFFIRM study, 20-30% of patients with permanent AF do not achieve HR control.²⁴ Several case reports^25-28 and one randomized placebo controlled study²⁹ detailing their experiences with ivabradine for HR control in AF patients, consistently showed its usefulness without significant adverse effects. Our study further demonstrates the feasibility of ivabradine in reducing HR in patients with AF-RVR, even in cases involving hypotension or respiratory failure requiring ventilator support. Although the US FDA and Taiwan Central Health Insurance Agency approved the use of ivabradine for patients with chronic stable HF with sinus rhythm but not for those with AF, our study included 69.6% of AF patients with acute NYHA functional class IV HF. In addition, 60.9% of the patients underwent endotracheal intubation and required ventilatory support, with more than 60% experiencing hypotension necessitating vasopressor treatment. Despite these challenges, our study demonstrates that ivabradine treatment had a beneficial effect, enabling most patients to recover and be discharged from the hospital.

The treatment protocol in managing patients with AF-RVR included initial slow intravenous amiodarone 150 mg followed by continuous amiodarone infusion. Beta-blockers were commonly used if there was no contraindication. Diltiazem might be used if patient could not take beta-blocker due to a contraindication or other causes. Ivabradine was also used if HR was still ≥ 100 bpm. According to this treatment protocol, the decrease in HR cannot simply be attributed to ivabradine use, other medications may also have contributed to the rapid control of the patients’ tachycardia.

Several limitations of this study should be acknowledged. First, the number of patients in this study was small. Further investigations including a large number of patients, and especially those with functional class IV, and randomized studies may be warranted to clarify whether ivabradine is useful in severely decompensated HF patients. Second, a previous meta-analysis suggested a potential association between long-term ivabradine use and the development of AF in patients with sinus rhythm.³⁰ However, our study primarily aimed to assess the short-term effect on HR reduction, and long-term side effects were not within the scope of this investigation.

New knowledge gained

1. Ivabradine treatment may be feasible in critically ill patients with AF-RVR, showing no side effects, even in cases of acute functional class IV heart failure.

2. The time taken for ivabradine to reduce HR to 80 bpm, referred to as "Time to 80", might be a useful clinical indicator of poor prognosis in AF patients who had acute HF and tachycardia.

CONCLUSIONS

This study demonstrated that in addition to usual treatment, adding ivabradine might be feasible in critically ill patients with AF-RVR without causing side effects. Since HR reduction is beneficial to patient outcome, our data demonstrated that the surviving patients tended to have a significantly shorter "Time to 80" compared to those who did not survive, suggesting that "Time to 80" might be a useful clinical indicator of poor prognosis in critically ill patients with AF-RVR. However, further investigations involving a larger patient cohort are needed to verify its clinical utility.

DECLARATION OF CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest.