In the present study we assessed LMWH dosing practices in 364 cardiovascular inpatients (376 admissions) and identified the efficacy and safety of LMWH treatment in 312 cases as measured by major adverse vascular events and major bleeding. There is a considerable disparity in LMWH use when comparing clinical practice to the guideline . Seventeen percent of patients (64/376) without body weight records received LMWH, 10.9% (34/312) of patients received the recommended doses of LMWH and 87.8% (274/312) received underdoses of LMWH. Interestingly, we found that receiving underdoses of LMWH was not a risk factor for major adverse vascular events. The only risk factor for major adverse vascular events was severe RI.
LMWHs are prescribed based on the patient’s weight according to dose-finding studies. However, accurate weight assessment is a challenge for seriously ill patients that are due to the limitations of resources, physical space and time . In our study, we found that approximately 1 in 6 patients received LMWHs without having a record of weight. This is similar to a previous study reported that approximately 1 in 10 patients received enoxaparin for treatment of an ACS without weight documentation . Furthermore, it has been reported that estimation of patients’ weights by health care providers is inaccurate having a mean error of 9 to 10 kg . Inappropriate dosing of LMWH can easily occur if the weight is estimated incorrectly, which can lead to medication errors in clinical practice. However, studies of the consequences of inappropriate dosing of LMWHs in real world practices are still scarce.
The major complication of anticoagulant and thrombolytic therapy is bleeding. A previous study demonstrated that patients with ACS often received excess doses of LMWH that was accompanied by an increased risk of major bleeding . In order to decrease the risk of bleeding, some clinicians in China often prefer to choose empirical dose strategies when administering LMWHs instead of those reported in the results of clinical trials or suggested by Chinese guidelines. In our hospital, the most commonly adopted dosing strategies are enoxaparin 4,000AxaIU, nadroparin 4,100AxaIU or dalteparin 5,000AxaIU given twice daily when a patient’s weight is < 80 kg. For patients that weigh ≥ 80 kg, enoxaparin 6,000AxaIU, nadroparin 6,200AxaIU or dalteparin 7,500AxaIU are given twice daily. These dosing strategies reflected the reason for the high rate of LMWH underdosing in the current study. As a result, there were no major bleeding events in our study; conversely, the rate of major bleeding events has been found to be approximately 1–6.5% in clinical trials of LMWHs [9–11]. Therefore, the practice of underdosing LMWH done in our hospital appears to be safe.
Unlike excess dosing of LMWH, which is related to a risk of bleeding, foremost concern associated with underdose of LMWH is the risk of embolism. Thus, we determined the efficacy of the current dosing practice of LMWHs, as measured by the incidence of embolism. Surprisingly, in the underdose LMWH group, the incidence of major adverse vascular events was similar to that of the group receiving the recommended dose (2.6% vs. 2.9%). Previous data have demonstrated that patients with low anti-Xa activity increased 30-day mortality . This may be due to the fact that the underdose of LMWH in our study doesn’t indicate low anti-Xa activity as LMWH has linear pharmacokinetics but high between-subject variability [20, 21]. On the other hand, clinical outcomes are also influenced by patients’ characteristics and not only the dosage of LMWH. In the above mentioned study, patients with sub-therapeutic anti-Xa levels were significantly older, and had more impaired renal function and inferior heart function compared with others . However, in our study, patients that received underdoses of LMWH had better baseline characteristics (younger and better renal function) than the recommended and excess dose groups; this may be the primary reason that the underdosing of LMWH was not found to be a risk factor for embolism in our study.
Since there were no severe RI patients receiving underdoses of LMWH, a fixed and weight-independent dosage may be not suitable for severe RI patients. LMWHs are not recommended for use in patients with severe RI due to the risk of accumulation may lead to major bleeding [11, 22, 23]. According to the results of the ExTRACT-TIMI 25 trial , a dose of 1 mg/kg of enoxaparin every 24 h was recommended for patients with an estimated creatinine clearance <30 ml/min. However, in our study, major adverse vascular events occurred more often in severe RI patients than in patients with creatine clearance ≥30 ml/min (30% vs. 1.3%, P < 0.001), although 57.1% (4/7) of severe RI patients receiving excess doses of LMWH. After multivariable analysis, we found that severe RI is the only predictor of major adverse vascular events. In elderly patients (≥75 years), STEMI patients, excess doses of LMWH were not independent predictors of major adverse vascular events. Results from the current study are consistent with those from previous studies in which patients with RI have a higher risk for thromboembolic complications [24–26], and support the recommendation for dose adjustments based on anti-Xa activity and not calculated based on a simple dose scheme for LMWH used in RI patients . Our results indicate that using LMWH at a fixed, lower dose in patients without severe RI may be safe and effective.
Nevertheless, there are some limitations to this study. First, our findings are based on the results of a one-center, retrospective study, complementing the prospect and lack of follow-up. Second, unlike randomized trials that have more restrictive inclusion criteria, it must be noted that the patient characteristics in this study were not as well-controlled. Third, due to a lack of anti-Xa assay in our hospital, we could not measure anti-Xa activity in RI patients. Finally, small sample size is a potential limiting factor in this study as well.