Prior beta-blocker treatment improves outcomes in out-of-hospital cardiac arrest patients with non-shockable rhythms

The prognosis of out of cardiac arrest is poor and most cardiac arrest patients suffered from the non-shockable rhythm especially in patients without pre-existing cardiovascular diseases and medication prescription. Beta-blocker (ß-blocker) therapy has been shown to improve outcomes in cardiovascular diseases such as heart failure, ischemia related cardiac, and brain injuries. Therefore, we investigated whether prior ß-blockers use was associated with reduced mortality in patients with cardiac arrest and non-shockable rhythm. We conducted a population-based retrospective cohort study using multivariate propensity score–based regression to control for differences among patients with cardiac arrest. A total of 104,568 adult patients suffering a non-traumatic and non-shockable rhythm cardiac arrest between 2005 and 2011 were identified. ß-blocker prescription at least 30 days prior to the cardiac arrest event was defines as the ß-blockers group. We chose 12.5 mg carvedilol as the cut-off value and defined greater or equal to carvedilol 12.5 mg per day and its equivalent dose as high-dose group. After multivariate propensity score–based logistic regression analysis, patients with prior ß-blockers use were associated with better 1-year survival [adjusted odds ratio (OR), 1.15, 95% confidence interval (CI) 1.01–1.30; P = 0.031]. Compared to non-ß-blocker use group and prior low-dose ß-blockers use group, prior high-dose ß-blockers use group was associated with higher mechanical ventilator wean success rate (adjusted OR 1.19, 95% CI 1.01–1.41, P = 0.042). In conclusion, prior high dose ß-blockers use was associated with a better 1-year survival and higher weaning rate in patients with non-shockable cardiac arrest.

Patient selection and follow-up. The study population included all patients receiving cardiopulmonary resuscitation (CPR) at the emergency room. These patients would be coded with a procedure code "47029c". To appropriately select post-cardiac arrest patients, patients with (1) non-level 1 triage, (2) trauma-related event experience, (3) more than 6 h stay in emergency room, (4) shockable rhythm, and (5) < 18 years old were excluded from the study (Fig. 1). Patients presenting to emergency room in Taiwan are allocated a triage category based on the time in which they need medical attention. People who need to have treatment immediately or within two minutes are categorized as Level 1(resuscitation) and they are in an immediately life-threatening condition. Reportedly, only 3.9% of patients were assigned into levels 1 10 . Previous study revealed that the hospital mortality was associated with the ER boarding time. Patients stayed longer than 6 h in emergency room (coded in our National Health Insurance Research Database (NHIRD) were excluded to minimize the confounding effects of inadequate post-cardiac arrest care 11 . www.nature.com/scientificreports/ Patients were followed-up from the index date of cardiac arrest until 1-year survival or death. The "β-blocker group" is composed of cardiac arrest patients using β-blockers continuously for at least 30 days before the index date. Patients without β-blocker use in the 30 days before the cardiac arrest event were included in the control group or "non-β-blocker group." To investigate the dose effect of β-blockers on the 1-year survival in these patients, they were categorized to high-dose if the mean daily dose was greater or equal to carvedilol 12.5 mg or its equivalent dose. The Taiwan National Health Research Institute definitions of urbanization, hospital classification, and qualifications of medical center criteria have been previously described 12,13 (Fig. 1).
Outcome measures. The primary end point was 1-year survival. Additional clinical outcomes included survival to ICU admission and survival to discharge. The functional outcomes measured were ventilator wean success rate at 1 month. Statistical analysis. Descriptive statistics were computed for the categorical and continuous variables. We compared baseline characteristics of the 2 groups using the χ 2 test for categorical variables and the t test for continuous variables. In addition to sex and age at index date, comorbidities at baseline and 1-year period were extracted from both outpatient and inpatient records and classified according to the Deyo-Charlson Comorbidity Index (Deyo-CCI) 14 .
Patients in the β-blocker and non-β-blocker groups were then matched by Propensity score (PS) at a 1:1 ratio sampling without replacement to reduce selection bias between the groups. Table 1 showed the results of logistic regression for PS estimation. Kaplan-Meier survival curves were analyzed using the stratified log-rank test to evaluate the β-blockers beneficial effect on 1-year survival. If the imbalance existed after PS matching, multivariate logistic regression analysis after PS matching (double-adjustment) could be performed to remove confounding 15,16 . The independent effects of prior β-blocker use on 1-year survival were analyzed by multivariate PS-based logistic regression analysis. The model was adjusted by potential confounders such as age, sex, drug use, CCI scores, underlying comorbidities like HTN, diabetes, coronary artery disease, congestive heart failure, atrial fibrillation, CKD, malignancy, COPD and asthma, urbanization level, the event year, resuscitation in medical center, hypothermia therapy, and achieved of coronary angiography. Subgroup analyses of 1-year survival were used for β-blockers and non-β-blockers groups based on clinical characteristics such as age, gender, CCI scores, diabetes mellitus, hypertension, dyslipidemia, CAD, CHF, atrial fibrillation, CKD, COPD and asthma. Differing criteria in sensitivity analysis were used to validate regression model findings. All analyses were performed with SAS software, version 9.4 (SAS Institute, Inc., Cary, North Carolina). All p-values reported were 2-tailed, and the significant level was set at < 0.05.

Results
Overall, 104,568 patients were included in the analysis (Fig. 1), of which, 13,880 patients (13.3%) were β-blocker users. Patients in the β-blocker group had more comorbidities such as hypertension, diabetes malleus, coronary artery disease, congestive heart failure, and chronic kidney disease. Conversely, several patients in the control group had a history of malignancy, COPD, and asthma. The CCI score was higher and procedures for coronary angiography were performed more often in the β-blocker group. After PS matching, no significant differences in most comorbidities, gender, or year of resuscitation were noted between these groups except that patients in the non-β-blocker group were older, more hypertensive, had history of COPD, and less coronary artery disease. Our results showed that the survival to ICU admission (25.7% vs. 23.1%; P < 0.0001), survival to hospital discharge (15.5% vs. 13.7%; P < 0.0001), and 1-year survival (4.2% vs. 3.7%; P = 0.02) were better in the prior β-blocker use group after PS matching ( Table 2). The Kaplan-Meier survival curve demonstrated better 1-year survival in the prior β-blockers use group ( Fig. 2A, stratified log-rank test; P < 0.0001).
Under the multivariate PS-based logistic regression analysis, patients with prior ß-blockers use were associated with better 1-year survival under the (OR, 1.15, 95% CI 1.01-1.30; P = 0.031) after adjusting age, gender, medications use such as antiplatelet agents and ACEI/ARB, CCI scores, clinical covariates such as diabetes mellitus, hypertension, dyslipidemia, CAD, CHF, atrial fibrillation, CKD, COPD, urbanization level, the event year and the management of cardiac arrest (Table 3). A beneficial outcome of 1-year survival was observed for patients who were younger, were females, had a history of COPD, and had higher CCI scores (Table 3). Cardiac resuscitation that was performed at the medical center and required a lower amount of adrenaline (epinephrine) was associated with better chances of 1-year survival. In comparison to those who did not undergo coronary angiography, patients who underwent coronary angiography during hospitalization also had better chances of 1-year survival.
The mean daily dose in both groups is listed in Table 4. After using Carvedilol 12.5 mg and its equivalent dose as cutoff value, the mean daily dose greater or equal to Carvedilol 12.5 mg (or its equivalent dose) was defined as high-dose group. After multivariate PS-based logistic regression analysis, both patients in the highdose (n = 7021) and low-dose (n = 6859) prior β-blockers use groups had greater odds of survival to hospital admission (adjusted OR: 1.16, 95% CI 1.09-1.25, P < 0.0001 and adjusted OR: 1.08, 95% CI 1.01-1.16, P = 0.0216, respectively ) and survival to discharge (adjusted OR: 1.18, 95% CI 1.09-1.28, P < 0.0001, and adjusted OR: 1.04, 95% CI 0.95-1.13, P = 0.41, respectively) than those in the control group. In addition, the high-dose prior β-blockers use group had better chance of 1-year survival (adjusted OR: 1.27, 95% CI 1.09-1.47, P = 0.0021) and higher ventilator wean rate (adjusted OR: 1.19, 95% CI 1.01-1.411, P = 0.0423) than the control group after multivariate PS-based logistic regression analysis (Fig. 2B).
Also, subgroup analysis was performed in patients with prior β-blockers use, we found that compared to patents with prior β-blockers use and younger than 70 years old, patients with prior β-blocker use and more than 70 years old are associated with a better 1-year survival. (adjusted OR: 1.12 vs.  (Fig. 3). Further large multicenter prospective studies are required to verify the better 1-year survival outcome of prior β-blocker use in patients > 70 years old, with history of HTN, diabetes, COPD or CCI score > 3. As shown in Table 5, sensitivity analysis excluded patients with comorbidities such as COPD, asthma or malignancy, prior to cardiac arrest. Patients receiving no epinephrine or only 1 dose (due to rhythm conversion, without resorting to anti-arrhythmic agents) were also excluded in the sensitivity analysis. The relationships between high-or low-dose β-blocker treatment and 1-year survival, as well as survival to ICU admission and survival to hospital discharge, remained consistent.

Discussion
Our nationwide cohort study showed that a greater odd of better 1-year survival and higher weaning rate of ventilator were observed in the prior high-dose β-blocker use group under the multivariate PS-matched regression analysis method. Reportedly, the chance of 1-year survival after cardiac arrest was higher in patients with favorable neurologic outcomes at hospital discharge 17 . From our analysis of ventilator wean rates, pre-β-blocker use not only improved the long-term clinical outcome but also improved the immediate functional outcomes after cardiac arrest. Better outcomes of previous ß-blockers use in patients with non-shockable cardiac arrest were unchanged even after sensitivity analysis. The Charlson Comorbidity Index (CCI) score is a measure of the burden of disease arising from multiple comorbidities and a higher CCI score was associated with greater mortality risk 18 . The existence of some comorbidity may trigger the initiation of appropriate therapy to reduce that mortality risk. High CCI scores might be associated with more intensive treatment, and this could lead to inadequate prediction of 1-year survival due to the presence of a treatment paradox 19 .
Cardiac arrest patients experience post cardiac arrest syndrome, which comprises anoxic brain injury, post cardiac arrest myocardial dysfunction, the global ischemic-reperfusion injuries, and responsible for mortality and morbidity in these patients 20 . Cessation of blood circulation leads to ischemia reperfusion injuries in major organs, including the brain and the heart. The ischemic event initiates a cascade of circulating inflammatory www.nature.com/scientificreports/ cytokines, resulting in excessive sympathoadrenal activation and endothelial damage. The pathological sympathetic activation after acute ischemic stroke has been repeatedly observed in acute stroke and is related to poorer outcomes 21 .β-blockers use before ischemia-related brain injuries showed beneficial effects including a milder stroke severity and lower mortality 22 . In animal models, β-blockers administered before the induction of experimental ischemia lead to a reduction in infarct volume by 40% 23 . The high susceptibility to pneumonia caused by the sympathetic activation in post-stroke immunosuppression has been extensively discussed. Stroke treatment with β-blockers has been associated with reduced mortality 24 . Several studies have shown the protective effect of β-blockers on ischemia-related cardiac injury 23,24 . The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II) trial, the first efficacy trial investigating all-cause mortality in patients with chronic heart failure on β-blocker therapy, showed a 32% risk reduction in total mortality 25 . The use of pre-procedural β-blockers was associated with a lower risk of in-hospital cardiac death in patients with acute coronary syndrome undergoing percutaneous coronary intervention 26 . The perioperative cardioprotective effect made by β-blockers may be multifactorial. First, the negative inotropic and chronotropic effects made byβ-blockers decrease myocardial oxygen demand. Also, β-blockers could modulate myocardial inflammatory responses such as cytokine release and leukocyte recruitment 27 . Moreover, the myocardial metabolism was shift from fatty acid oxidation toward glucose uptake 28 . Therefore, it is reasonable to suggest that prior β-blockers use Table 3. Univariate and multivariate logistic analysis for factors related to one-year survival outcomes in after propensity score-1:1 match groups. www.nature.com/scientificreports/ might mitigate the magnitude of post cardiac arrest syndrome, which results in improved clinical and functional outcomes and overall performance survival. Prior systematic review of clinical trials about ß-blockers use in patients with heart failure has established higher dose ß-blocker does not ameliorate better outcomes 29 . Take CIBIS II study for example, the reduced mortality with bisoprolol was little different regardless of the dose level (high dose (10 mg/day), moderate dose Table 4. The mean daily dose use of ß-blocker in both high dose and low dose group after propensity score matching. we defined the mean daily dose greater or equal to Carvedilol 12.5 mg qd and its equivalent dose as high dose group.    30 . The incidence and severity of adverse drug effects are often dose related. ß-blockers can be effective in lower dose. In our high dose prior β-blockers use group, the mean daily dose was 4.4 mg (bisoprolol) or 25.6 mg (carvedilol). But the mean daily dose in low dose prior β-blockers use group was only 1.8 mg (bisoprolol) or 1.8 mg (carvedilol). The insufficient dose of ß-blocker use might explain the insignificant survival benefit in the low dose ß-blocker group. The study has some limitations. Detailed neurologic outcomes were not available from the NHIRD. Instead, we evaluated the overall performance outcomes by ventilator wean success rate at 1 month. Also, resuscitation information at the area of occurrence was not accessible. However, the quality of resuscitation performance was not related to the prior use of β-blockers.

Conclusion
In conclusion, patients with prior high-dose ß-blockers use before cardiac arrest are associated with better chance of 1-year survival and higher weaning rate in a propensity score-matched nationwide cohort study. Further large multicenter prospective studies are required to confirm whether prior ß-blockers use before cardiac arrest leads to improved clinical outcomes in cardiac arrest patients with non-shockable rhythm.

Data availability
The dataset used and analyzed during the current study are available from the corresponding author on reasonable request.