The data obtained from the USA multi-centre database in this study cohort indicate that approximately 30–40% of patients experiencing CA succumb to their condition while in the ICU, and 40–50% pass away within the hospital after spontaneous circulation returns. These findings are consistent with those of previous studies [1, 22]. Furthermore, there was a higher proportion of male patients in this cohort, with 55.6% admitted through the emergency department following an out-of-hospital CA event. Unfortunately, information regarding the initial heart rate and witness status remains unknown. Nevertheless, logistic regression analysis conducted on retrospective cohort data suggested that heparin anticoagulants are protective factors of ICU and hospital mortality factors in patients with CA. Importantly, these results remained consistent even when comparing the alive and expired groups based on routine prognostic factors identified by PSM. No significant differences were observed regarding the mortality risk or survival time between the UFH and LMWH groups.
Numerous studies have consistently reported favourable thrombolysis outcomes when managing patients with CA, particularly CAs possibly caused by a pulmonary embolism [16, 24, 25]. However, bleeding complications associated with this treatment modality are relatively high [17, 24]. Consequently, thrombolysis cannot be a routine CA intervention in clinical practice. Some researchers involved in pulmonary embolism have stated that anticoagulant therapy presents a lower bleeding complication risk than thrombolysis therapy [26, 27]. Although bleeding remains the most common adverse event associated with heparin administration, research has demonstrated that its use does not significantly increase the haemorrhage risk in patients experiencing CA [28, 29]. Therefore, there is potential for utilizing heparin anticoagulants as a standard therapeutic approach for cerebral resuscitation in individuals with CA.
Animal experimental study results have demonstrated prompt detection of microthrombus formation in cerebral microvessels within 5–10 min following CA [20]. Microthrombus formation, microcirculation disturbances, and the nerve cell injury cascade after secondary tissue ischemia, hypoxia, and oxygen metabolism disruption influence the prognosis of CA nerve function [30–32]. Simultaneously, systemic microthrombi formation constitutes a pivotal mechanism that affects tissue oxygen metabolism and induces organ dysfunction [31]. Resolving the effects of microthrombi on various organs in patients with CA may constitute a crucial mechanism for anticoagulation therapy to enhance their prognosis. Furthermore, thrombosis in the coronary or pulmonary arteries can be identified as a causative factor of CA [12]. The anticoagulant effect of heparin has a favourable impact on myocardial or pulmonary artery infarction amelioration. Furthermore, heparin use is not contraindicated in patients with CA.
Although no guidelines currently recommend heparin as a standard treatment for patients with CA, its role in managing ACS, a common underlying cause of CA, remains unclear. Based on evidence from a cohort study lacking randomized controlled trials, the 2018 European Society of Cardiology/European Association for Cardio-Thoracic Surgery Guidelines [28] on myocardial revascularization propose that intravenous UFH may be considered more appropriate as an anticoagulant therapy for patients with cardiogenic shock, like those without cardiogenic shock, before, during, or after percutaneous coronary intervention (PCI). A 70–100 U/kg UFH intravenous bolus is recommended as the standard anticoagulant for PCI in non-ST-segment elevation ACS and ST-segment elevation myocardial infarction (STEMI). However, during targeted temperature management, the heparin infusion duration should be prolonged, and activated clotting time changes should be monitored [28] or heparin discontinuation should be considered [19]. Another randomized controlled study demonstrated comparable rates of death and major bleeding between bivalirudin and UFH in patients with ACS susceptible to hemodynamic or electrical disorders. However, further analysis using borderline interaction testing revealed superior bivalirudin benefits [33]. A retrospective study conducted by Ulrich Grabmaier from Germany involving 384 patients demonstrated significant survival rate improvement of patients with out-of-hospital CA receiving AH [22]. The survival rate has increased from 34–59.4%. The regression model identified AH as an independent survival predictor at discharge [HR 0.60 (0.44–0.82), P = 0.002] [22]. In this study cohort, 16.54% of patients received heparin anticoagulant treatment. The ICU survival rate for patients receiving anticoagulants was 68.21%, and the final discharge survival rate was 60.06%, approximately 10% higher than that of the non-anticoagulant group (49.29%). After adjusting for age, sex, disease severity score, initial rhythm, and witnesses, anticoagulant therapy significantly improved survival at discharge by approximately 7%. These findings were consistent with those of Grabmaier et al.
Furthermore, the results of this study suggest that antiplatelet therapy has a protective effect against ICU and hospital mortality in patients with CA. The results after PSM indicate an association between antiplatelet therapy and reduced risk of ICU death [OR: 0.58 (0.39–0.87), P = 0.008], as well as reduced hospital mortality risk [OR: 0.68 (0.46–0.99), P = 0.043]. However, subgroup analysis indicated that anticoagulant therapy did not provide significant prognostic advantages in patients with concurrent antiplatelet drug administration during CA. Notably, the observed protective effect was more prominent in patients not receiving concomitant antiplatelet therapy. Similarly, no statistically significant protective effects were observed within the cohort of individuals diagnosed with ACS encompassing STEMI, non-STEMI, or unstable angina.
Nevertheless, comparatively advantageous outcomes were observed in patients without ACS. This finding can be ascribed to the necessity of early and prolonged antiplatelet medication administration in most patients with ACS. Additionally, Elmer et al. [34] conducted a retrospective cohort study involving 1,054 prehospital CA patients, which revealed that administering antiplatelet therapy before hospitalization was associated with higher rates of discharge survival and improved neurological outcomes than anticoagulant therapy. The limited duration of anticoagulant administration before hospitalization may impede attaining optimal anticoagulation efficacy, necessitating further analysis and large-scale randomized controlled trials to elucidate the potential synergistic effects of anticoagulants and antiplatelet drugs in patients with cardiovascular disease.
This study demonstrated a higher prevalence of UFH usage than LMWH in the cohort, with few patients transitioning from UFH to LMWH treatment. Heparin anticoagulants are primarily employed for preventing venous thrombosis, their application during hemodynamic monitoring, and in patients with renal insufficiency undergoing blood purification. A small proportion of heparin anticoagulant use was observed for managing CA resulting from pulmonary embolism and other thrombotic events. UFH and LMWH differ significantly in terms of their molecular weights, mechanisms of action, pharmacokinetics, and adverse reaction risk profiles [35]. UFH activity extends to various thrombin enzymes and encompasses platelets, exhibiting a shorter half-life, lower bioavailability, and increased bleeding risk [36]. This study investigated the impact of the clinical outcomes between the two heparins to elucidate any potential efficacy disparities further. The findings revealed no significant differences in ICU, in-hospital, or survival mortality. However, UFH demonstrated a lower ICU and hospital mortality incidence and an extended survival period than LMWH. Furthermore, this disparity was more pronounced with the consistent administration of both forms. Nevertheless, owing to the limited sample size within the continuous usage group for both heparins, larger-scale studies and prospective randomized controlled trials are warranted to clarify the synergistic effects of UFH and LMWH further.
The limitations of this study are as follows. (1) Employing heparin anticoagulation for various indications, with significant variations in the frequency, dosage, and administration duration, making it challenging to obtain accurate total dosages for each sample and limit the dose-effect analysis. (2) Due to data constraints, this study was unable to establish a causal relationship between heparin use and specific bleeding complications; thus, no comparisons could be made regarding bleeding-related adverse events. (3) Coagulation status, D-dimer levels, and other relevant indicators may directly affect heparin administration in patients, while the thrombosis risk score can serve as a crucial basis for preventing deep vein thrombosis. However, distributing these factors among different groups, their influence on heparin use, and their subsequent outcomes constitute a complex topic that is beyond the scope of this study and requires further investigation. (4) The neurological function prognosis is another critical clinical outcome for patients with CA. This study did not investigate the association between anticoagulants and neurological function prognoses.