In this study, patients in the heparin group had significantly improved neurological outcomes (GCS score), ICU mortality, hospital mortality, and survival time compared with those in the non-heparin group. There was no significant difference in the prognosis of some neurological outcomes (spontaneous-adequate ventilation, dementia, and persistent vegetative status). There was no significant difference between the UFH group and the LMWH group for these clinical outcomes.
The study cohort was from a United States database. Data show that approximately 30–40% of hospitalized cardiac arrest patients die in the ICU and 40–50% die in the hospital, which is consistent with previous reports [1, 20]. Because the guidelines do not recommend heparin for the treatment of cardiac arrest, only 18.43% (1105 patients) in this cohort received heparin for a variety of reasons, and UFH use was about twice as high as LMWH use. In a retrospective study of 384 patients by Grabmaier and his colleagues, the use of AH in patients with out-of-hospital cardiac arrest improved survival from 34–59.4%. AH was found to be an independent predictor of discharge survival in the regression model (hazard ratio 0.60 [0.44–0.82], P = 0.002) [20]. In this study, the survival rate of the control group was 44.79%, higher than that of the placebo group in the previous study by Grabmaier, and the final discharge survival rate of the heparin group was 59.58%, which was similar to that of the AH group in the Grabmaier study. Although some studies have suggested that the combination of anticoagulant and antiplatelet is not necessary for most situations, the combination of the two studies suggests that the combination of anticoagulant and antiplatelet may improve patient and clinical outcomes. If the treatment levels in the two studies were similar, aspirin’s contribution to survival would be about 10%, and heparin’s contribution to survival would be about 15%, without taking into consideration any cross-actions. More rigorous prospective, double-blind, crossover studies are needed to further clarify the separate effects of aspirin and heparin and whether there is a synergistic interaction between them. In addition, the current study found that heparin significantly extended the survival time of patients with cardiac arrest, which has not been reported in previous studies; however, heparin patients also had longer hospital stays.
Neurological outcome is another important clinical outcome in patients with cardiac arrest. The maximum GCS score during the disease was used to evaluate the patient’s state of consciousness. Both the mean value of the maximum GCS and the mean value of each item (motor, verbal, or eyes) were better in the heparin group. A stratified GCS analysis also showed that the heparin group had a higher ratio of good cerebral performance (GCS score of 13–15) (62.7% vs. 58.84%). Moreover, Grabmaier’s research showed that pre-hospital AH administration was associated with favorable neurological outcomes (odds ratio [OR] 2.25 [1.31–3.87], P = 0.003). Patients with AH were more likely to gain return of the spontaneous circulation (OR 2.22 [1.45–3.42], P < 0.001) [19]. However, it was also found that the incidence of changed mental status, encephalopathy (post-anoxic), seizures, and the duration of mechanical ventilation was longer in the heparin group. This may be associated with an increase in the survival rate of patients who do not have a good neurological outcome under current treatment but whose prognosis is clearly better than that of death.
As common anticoagulants, in addition to large differences in molecular weight, UFH and LMWH also have large differences in terms of mechanism of action, pharmacokinetics, and risk of adverse reactions [22]. UFH can act on variety of thrombin enzymes and can also act on platelets, which have a shorter half-life, lower bioavailability, and pose a higher risk of bleeding [23]. To further determine whether there is a difference between the two types of heparin, we investigated their effects on clinical outcomes. The results showed that there was no significant difference in the major clinical and neurological outcomes between the two groups. However, UFH was associated with a tendency towards lower ICU and hospital mortality rates compared to LMWH. The same trend was observed for GCS scores. Whether this trend is related to the antiplatelet effect of ordinary heparin needs further study. Because we did not analyze bleeding-related complications, it is unclear whether the common heparin group had a higher risk of bleeding. However, Grabmaier's study showed that AH did not increase the risk of bleeding in patients with cardiac arrest [19].
Animal studies have shown that a marked activation of blood coagulation occurs and that microthrombi are found in the cerebral vessels after a cardiac arrest of 5 to 10 min [18]. Microthrombosis, microcirculation disorder, secondary tissue ischemia and hypoxia, and oxygen metabolism disorder followed by a series of nerve cell injury are some of the important influences on the neurological prognosis of cardiac arrest [24–26], and the formation of systemic microthrombosis is also an important mechanism affecting tissue oxygen metabolism and organ function damage [25]. Resolving the influence of microthrombosis on various organs of cardiac arrest may be an important mechanism for heparin to improve the prognosis of cardiac arrest patients. In addition, the cause of cardiac arrest in most patients is related to thrombosis of blood vessels in the heart or lungs [11]. Furthermore, the anticoagulant and antiplatelet effects of heparin have a good effect on the improvement of heart or pulmonary vascular infarction. Cardiac arrest is not a contraindication to the use of heparin in clinical practice; however, the occurrence of bleeding complications is a concern. Interestingly, some studies have shown that heparin does not significantly increase the risk of bleeding in cardiac arrest [27, 28].
Our study had some limitations. First, heparin may be used for hemodialysis, thrombosis, hemodynamic monitoring, hypercoagulability, or disseminated intravascular coagulation; as this study was limited by data extraction, we could not analyze the reasons for administration of heparin. Second, when heparin anticoagulants are used for different reasons, the frequency, dose, and cycle of medication vary greatly; hence, the total dose of each sample was difficult to obtain, and the dose-response analysis was limited. Third, due to data limitations, we could not determine which bleeding complications were causally associated with heparin; therefore, no comparison of bleeding-related complications was made. Fourth, lack of heparin administration in some cases may stem from a decision to discontinue care due to poor prognosis. Data on the proportion of cases with limited or discontinued treatment because of poor prognosis was unavailable in the database. Finally, coagulation status, D-dimer, and other indicators may directly affect the use of heparin in some patients. Patients’ thrombosis risk score may also be an important basis for the prevention of deep vein thrombosis. The distribution of these factors among each group, the use of heparin, and the effect on outcomes represents a more complex interaction, and this was not covered in this study. Therefore, further research is needed.