Heparin was the most used agent, followed by Warfarin and its derivatives. Heparin, Warfarin, Enoxaparin were associated with shorter length of ICU stays and hospital stays and lower mortality events. These findings suggest that the use of all the thromboprophylaxis agents had comparable effects in ventilated patients and had a significant positive impact on the ICU-related outcomes in the study population. Also, the newer blood thinner, Enoxaparin, had lesser effect on the outcomes, contrary to expectations, and, perhaps, had slightly lower mortality or morbidity advantages compared to the older blood thinners such as Heparin and Warfarin (Table 2 &3). This finding contradicts the findings of a published study where Enoxaparin or Dalteparin were found at least as effective as unfractionated Heparin [13]. This study showed high use of thromboprophylaxis among ventilated patients (61.5%), comparable with other published studies, which reported overall thromboprophylaxis at 61.8% for all indicated patients during a hospital stay [14]. Also, the occurrences of pulmonary embolism, deep venous thrombosis (DVT) during the hospital stay were statistically significant for none of the blood thinners (Table 3). These findings are comparable with those of a previous study which did not find thromboprophylaxis prevents PE [15, 16]. Severe thrombocytopenia is a life-threatening complication, and can potentially cause internal bleeding, (e.g. intracerebral hemorrhage) if not treated. In this study, only Heparin was associated with serious thrombocytopenia episodes which required platelets transfusion (Table 4).
The number of individuals diagnosed with pulmonary embolism (n = 70) and DVT (n = 111) was small. Moreover, the occurrence of either pulmonary embolism or DVT did not vary significantly between any of the blood thinners studied (Table 2 &3). However, DVTs were more likely treated with Warfarin while pulmonary embolism patients were more likely to receive both Warfarin and Enoxaparin during their hospital stay (Table 2). These findings align with the contemporary clinical practice where the individuals who developed PE and DVT during the hospital stay are presumably switched or other thromboprophylactic agents are added. Also, higher D-dimer levels were not significantly associated with any of the blood thinners studied, although some studies have suggested that Heparin use might cause alterations in D-dimer levels (Table 4) [17]. These findings are comparable to findings in a a recently published review article, which included three randomized controlled trials (RCTs) held in ICU patients and concluded that the incidence of DVT was significantly lower in the thromboprophylaxis group in comparison to the control group, irrespective of the type of thromboprophylaxis used [18].
MIMIC-III (Medical Information Mart for Intensive Care III) is a large, freely available database comprised of deidentified health-related data associated with over 40,000 patients admitted in critical care units of the Beth Israel Deaconess Medical Center between 2001 and 2012 [19]. However, there are limitations regarding the history of prior oral anticoagulants use, such as Warfarin. The history of intake of Warfarin or other anticoagulants prior to ICU admission was not sufficiently documented in the database for useful analysis. Only 288 of the 4192 ventilated patients were on long-term anticoagulants prior to their admission, taking either Warfarin, Aspirin, or others. Moreover, no data on adequacy of dose, regularity of intake or their specific doses could be obtained. The study did not include the secondary analyses on patients with previous history of oral anticoagulant because of inadequate sample size and insufficient data. Furthermore, these patients probably represent patients at higher risk than others since they have two added risk factors for thromboembolism (ventilation and preexisting thromboembolic conditions). In these conditions, the authors had to assume that the practitioners routinely checked coagulation parameters to initiate, switch (oral to injectables), adjust dose or even stop blood thinners (Warfarin) temporarily during ventilation, within hours of their ICU admission. This study assumes all such decisions were properly taken at the ICU admission and stay. In all of the included ventilated patients in our study, the practitioners routinely checked coagulation profiles, which the authors used fair use assumption and did not investigate further in more details. Additionally, ventilated patients with prior use of oral blood thinners (n = 288) might have represented patients with an even higher risk of thrombosis during their ICU stay, when compared to the rest of the ventilated patients (n = 3904), owing to the presence of multiple risk factors for thromboembolism.
The treatment groups did not show any significant difference in their baseline SOFA scores among ventilated patients. Other ICU mortality scoring methods, such as APACHE, were not selected for analysis in this study due to the lack of sufficient and reliable data on their admission diagnosis at the ICU. In contrast, SOFA scores do not need those admission diagnosis parameters. Additionally, unlike the delta-SOFA score, the application of improvement of APACHE score or any other ICU mortality scoring system has not been addressed sufficiently in published literature [11]. The validity of using delta SOFA scores in our study is further supported in survival plots (Figs. 1 and 2), which reveal the association of higher SOFA scores with higher mortality rates. Consequently, SOFA scores and their improvement (delta SOFA) on days 4, 7 and 10 were chosen for analysis in this study. Furthermore, the STROBE statement requirements were fulfilled in this study [20].
Critical care patients are complex in their physiological derangements and often have multiple diagnoses at or after their admission. The comorbidity score also has a major contribution to the APACHE scoring systems. In APACHE, morbidity scores are derived from the presence of chronic comorbidities such as hepatic failure, immunosuppression, lymphoma, leukemia, metastasis, etc. recorded at or within 24 hours of ICU admission, some of which are based on subjective assessment (provisional diagnoses). These admission diagnoses are complex and are not accurately recorded with proper ICD-9 codes in the MIMIC database [21, 22]. In the included patients, only a limited number (n = 169) from admissions records (n = 495) were derived from SQL query reports (‘chartevents’ and ‘admissions’ records sections of the MIMIC database) had an admission diagnosis recorded with extractable ICD-9 code usable for APACHE scores calculation. The authors considered this as insufficient for this study. Likewise, a significant number of the participants (n = 1545) had unreliable or incomplete diagnosis codes (e.g. symptoms such as pain under evaluation, uncertain injury codes, procedures, provisional/suspected/rule-out diagnoses, ambiguous abbreviations, acute conditions such as electrolyte imbalances) recorded as their admission diagnosis in their records, and were recorded without proper ICD-9 codes. Furthermore, while comparing final diagnoses with admission diagnoses, chronic morbidities (such as chronic renal failure, metastasis) were ambiguous and were insufficiently documented at ICU admission day 1 (n = 14), which were more likely to have existed before their ICU admission in the participants [21].