This retrospective study investigated the role of different VTE prophylaxis modalities on the incidence of symptomatic VTE in neurocritical ill patients and the associated incidence of major bleedings. We observed no difference in the incidence of VTE between the administration of chemical prophylaxis versus the combination of chemical and mechanical prophylaxis. Though, the use of chemical only prophylaxis did result in a significantly lower risk of major bleedings. All other clinical outcomes of interest were not different between VTE prophylaxis strategies (i.e., ICU LOS, hospital LOS, and 28-day mortality).
There was no difference in baseline characteristics regarding the type of VTE prophylaxis in admitted patients with ischemic stroke between groups in our cohort. Patients admitted with ischemic stroke accounted for the majority of included patients with approximately 43.7% and 50%, in the chemical only and the combined prophylaxis group, respectively. Current guidelines recommend using chemical prophylaxis as soon as possible in acute ischemic stroke patients, except in patients with restricted mobility as the use of LMWH plus IPC is more preferred, mainly based on CLOTs 3 trial findings (2,16). These results are inconsistent with the results of the CLOTs 3 trial, which showed a 3.6% reduction in VTE with the use of IPC post-stroke (17). A fewer percentage of patients were admitted with the diagnosis of ICH accounted for 19.7% of the chemical prophylaxis group and 21.7% of the combination group in our cohort. Given the active bleeding status in this population, it is recommended to provide mechanical prophylaxis over chemical prophylaxis at the time of admission, except with stable hematomas where chemical prophylaxis could be administered after 48 hours of admission (2). In a large retrospective study, the utilization of chemical prophylaxis for ICH patients was very low, accounting for less than 20% of the total patients and <10% in the first two days of admission (18). The use of UFH was observed in 71.1% of the patients compared to enoxaparin which was used in 27.5%. This low compliance could have been caused by a lack of knowledge or safety concerns. Similarly, patients with an admission diagnosis of aSAH accounted for 4.7% of the chemical prophylaxis group and 8.6% of the combination group in our cohort. IPC is the recommended VTE strategy in this population and should be started immediately upon admission (2). UFH should be initiated as well unless in cases of unsecured ruptured aneurysms expected to undergo surgery (19). This may be extrapolated for patients undergoing endovascular treatment but data are not clear yet on this matter. In postoperative patients, UFH should be started within 24-hours as per guidelines recommendations. In a retrospective study investigating the timing of DVT in aSAH, the incidence of DVT peaked between day 5-9 of admission with a lower incidence of DVT in the group receiving heparin prophylaxis (19).
In patients with hemorrhagic stroke, early anticoagulation is associated with a significant reduction in PE, a non-significant reduction in DVT or death, and a non-significant increase in hematoma size (20). Moreover, TBI patients represented 10.7% of the chemical prophylaxis group compared to 19.5% of the combination group of the included patients. In this patient population, the use of IPC within 24 hours of presentation or 24 hours post craniotomy is recommended by the neurocritical society with reserving chemical prophylaxis for patients with TBI and ICH to be used within 24-48 hours, or 24 hours post craniotomy (2). In contrast, the American College of Chest Physicians (CHEST) guidelines recommend LMWH for major trauma patients unless contraindicated (21). The brain trauma foundation most recent guideline does not provide any strong recommendation for preference in VTE prophylaxis agent choice, dosing nor timing of administration (15). In addition, the recent clinical consensus from the American Association for the Surgery of Trauma (AAST) Critical Care Committee recommends initiating VTE prophylaxis within 24-72 hours depending on the stability of the intracranial and extracranial hemorrhages (22). These recommendations may explain the higher percentage of our patients in the combination therapy as they may have been started on mechanical prophylaxis initially then combined with chemical prophylaxis later. Previous guidelines also emphasized on the superiority of LMWH over UFH with low quality evidence.
In a retrospective cohort study conducted by Sauro et al in Canada, the adherence of current practice guidelines and the effect on clinical outcomes were evaluated in patients admitted to 10 different neuro, medical and surgical ICUs. Among neurocritically ill patients, chemical prophylaxis, mechanical prophylaxis and no prophylaxis was provided to 60.9%, 46.9% and 12.2%, respectively. Only 56% of the days spent in ICU were adherent to the practice guidelines. Specifically, concordance to guidelines when prescribing pharmacologic prophylaxis was reported in 26.6% of ICU days, whereas it was up to 80% of ICU days in patients eligible for mechanical prophylaxis. The results of this study demonstrate the variations and uncertainty regarding the optimal practices for prevention of VTE in neurocritically ill patients (23).
In this study, we observed an increase in the utilization of UFH compared to enoxaparin despite having normal baseline renal function. This observation is mainly attributed to the pharmacokinetic advantages of UFH over LMWH, especially with patients who underwent neurosurgical interventions during their ICU admission. UFH is more reasonable when acute interruption of anticoagulation is needed for emergent surgery or active bleeding event. Also, anticoagulation reversal can be better controlled with UFH when compared to enoxaparin achieved (24,25). The incidence of symptomatic VTE post-acute stroke was reported to have range of 2-10%, while we observed slightly an increased incidence in our population despite having 65% being categorized as low thrombotic risk based on their IMPROVE scores of <2 (2,19). This minimal increase may be a result of the late re-initiation of anticoagulation in patients who had an indication. Approximately 50% of our included patients had an indication for antithrombotic agent prior to admission, however 15% only were transitioned eventually to full anticoagulation in both groups. Additionally, the concomitant use of antiplatelets was lower than expected in the combined VTE modality group, given difference the likelihood of these patients carrying higher risk of bleeding upon admission. This is possibly due to their higher percentage of having surgical interventions during ICU admission (40% vs 56%; p: 0.051).
This study includes some limitations. First, we randomly selected neurocritically ill patients who were admitted to our institution during the study window. Therefore, we may have missed some patients in our data collection. Second, we have combined all neurocritical injuries in our cohort. This may limit the application of our findings to a specific neurocritical injury due to our heterogeneity. Further studies with a specific focus on one injury may better reflect the impact of different VTE prophylaxis modalities. Third, we did not collect data on thrombolytic use in acute ischemic stroke patients. We have very limited patients who present to our institution within the appropriate window for administration of such therapy (25). Availability of such data may better help explain the increased incidence of bleeding in one group or the other. Fourth, UFH was used more than LMWH in our cohort which may have contributed to the similar efficacy between the two groups. In the PREVAIL trial, the use of LMWH was associated with a reduction in VTE risk by 43% compared to UFH showing clear superiority in acute ischemic stroke patients (26). Lastly, we could not differentiate patients with a high or low risk of bleeding, as this would have only been achieved if better clinician documentation existed. However, up to our best knowledge there is no proven tool to predict or estimate the risk of bleeding in this patient population. More data will be needed to validate our findings in neurocritically ill patients.