LMWHs dosage and outcomes in acute pulmonary embolism with renal insufficiency, an analysis from a large real-world study

The CURES is an ongoing prospective, multicenter registry of consecutive patients presenting with subjectively confirmed PE with/without deep vein thrombosis (DVT). The study design has been previously reported [8]. PE was confirmed by helical computed tomographic pulmonary angiography (CTPA), ventilation-perfusion lung scintigraphy (V/Q scan) or pulmonary angiography. Patients identified high-risk PE (shock or systemic systolic blood pressure levels < 90 mmHg), CCr unable to be calculated on admission and undertook thrombolysis therapy as initial treatment were excluded.

Decisions on the treatment pattern such as to initiate, maintain, or change treatment were at the discretion of the physicians and patients. Patients’ data were collected using the electronic data capture system. Diagnostic methods and treatment of PE were at the discretion of attending physicians of the participating centers.

Demographic data, medical history related to venous thromboembolism (VTE), risk factors for VTE, symptoms and signs on presentation, physical and laboratory examination results, image test results, types of diagnostic methods, diagnostic results, therapeutic management and clinical outcomes of PE during hospitalization were collected.

The study was approved by institutional review boards and ethical committees of all the centers. Written informed consent was obtained from all the participants in the study according to the requirements of the ethical committee of each medical center.

The clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the 'Declaration of Istanbul on Organ Trafficking and Transplant Tourism'.

CCr was estimated at baseline by Cockcroft-Gault equation: CCr = (140—age) * (weight in kilograms) * (0.85 if female) / (72 * serum creatintine (in mg dL⁻¹)) [9]. Renal insufficiency was defined as CCr < 60 ml/min, and CCr < 30 ml/min was considered as severe renal insufficiency. PE severity was categorized according to the ESC/ERS guidelines to acute PE [6]. sPESI score was calculated for individuals accordingly [10]. A score point of 1 each was assigned for patients with any of the following conditions: age over 80 years, presence of cancer, chronic heart failure or chronic pulmonary disease, pulse rate ≥ 110 bpm, systolic blood pressure < 100 mmHg, and peripheral arterial oxygen saturation < 90% [10]. The total sPESI score was used to divide hemodynamically stable patients into intermediate-risk (sPESI ≥ 1) and low-risk patients (sPESI = 0). Considering the products of LMWH regimen (e.g., enoxaparin sodium, dalteparin sodium, nadroparin calcium) varied across different clinical centers, LMWH dosage was converted into IU/kg daily dose during data analysis and presented as adjusted dose (≤ 100 IU/kg/day) and conventional dose (> 100 IU/kg/day).

The primary endpoint of the study was in-hospital all-cause death. The secondary endpoints were (i) PE-related death, defined as death considered to be due to PE by autopsy or if the patients died shortly after objectively confirmed symptomatic PE and in the absence of alternative diagnosis [11]; (ii) Bleeding events, including major bleeding and clinically relevant non-major bleeding, were defined according to the criteria in the International Society of Thrombosis and Haemostatsis (ISTH) [12].

Baseline patient characteristics were expressed in terms of descriptive statistics. Categorical variables were summarized as frequency (percentage). Continuous variables were presented as mean (standard deviation, SD) or median (interquartile range, IQR). P values were calculated by students’ t test, χ2 test or Fisher exact test among different renal function groups/LMWH dose group where appropriate. Logistic regression, adjusting for age and gender, was performed to explore the odds ratios for adverse outcomes, including death, PE related death, bleeding and major bleeding, in patients with 30 ml/min ≤ CCr < 60 ml/min and CCr < 30 ml/min, compared to those with CCr ≥ 60 ml/min, respectively. Univariable and multivariable regression among patients with renal insufficiency (CCr < 60 ml/min) were performed to explore the risk factors for in-hospital bleeding events. Factors including adjusted LMWH dose, cancer and length of hospital stay were included into multivariable regression to estimate the odds ratios (OR) and 95% confidence intervals (95% CIs), taking both clinical value and statistical significance into consideration. Kaplan–Meier curves were drawn to compare the cumulative rates of all-cause death and PE-related death in patients with different renal function groups respectively, and compared by log-rank test. All tests were two-sided and were considered statistically significant at a p-value of < 0.05. All analyses were performed using SAS 9.4 software (Cary, NC, USA).

Among the CURES cohort, a total of 5870 non-high-risk PE patients were enrolled into analysis. 1311 (22.3%) patients were identified to have renal insufficiency in admission. Among those patients, 1191 (90.8%) were 30 ≤ CCr < 60 ml/min and 120 (9.2%) were CCr < 30 ml/min (Fig. 1). Characteristics of patients with renal insufficiency are demonstrated in Table 1.

The rates of all-cause death, PE-related death, bleeding and major bleeding were all higher in patients with renal insufficiency than those without renal insufficiency (Fig. 1). After adjustment of age and gender, 30 ≤ CCr < 60 ml/min was significantly associated with PE-related death (OR 2.10, 95%CI 1.02–4.31), bleeding (OR 1.78, 95%CI 1.27–2.50) and major bleeding (OR 2.71, 95%CI 1.54–4.75); severe renal insufficiency was significantly associated with all-cause death (OR 5.11, 95%CI 2.80–9.31) and PE-related death (OR 9.34, 95%CI 3.59–24.25) (Supplementary Figure S1). The cumulative all-cause death rate and PE-related death rate among patients with severe renal insufficiency were also significantly higher than other groups (both log-rank p < 0.0001) (Supplementary Figure S2).

LMWH has been applied commonly in renal insufficient patients, even among patients with severe renal insufficiency (91.2% in 30 ≤ CCr < 60 ml/min and 92.2% in CCr < 30 ml/min). UFH was used in 4.7% and 4.9% patients with moderate and severe renal insufficiency, respectively. DOACs were used in 3.1% and 2.0% patients with moderate and severe renal insufficiency, respectively. Fondaparinux was applied in 1.0%, both in patients with moderate and severe renal insufficiency (Fig. 2A). Patients with complete records of LMWH dose (N = 1042) were further analyzed: of the patients who were initially anticoagulated with LMWH, 273 (26.2%) were admitted adjusted dose and 769 (73.8%) were admitted conventional dose. 26.1% in 30 ≤ CCr < 60 ml/min and 26.2% in CCr < 30 ml/min were prescribed adjusted dose of LMWH (Fig. 2B).

Baseline characteristics were compared between the two groups of patients: those with older age, history of respiratory diseases, and more slight symptoms of PE were more likely to be prescribed adjusted LMWH (Supplementary Table S1). Bleeding events during hospitalization occurred significantly more frequently among those who were undertaken conventional dose of LMWH (9.2% vs 5.0%, p = 0.0466), major-bleeding rate was also higher among those patients, but the difference was not statistically significant (3.5% vs 2.1%, p = 0.3082). The rate of in-hospital all-cause death was significantly higher in those with adjusted dose of LMWH than conventional dose (5.5% vs 2.9%, p = 0.0434), the rates of PE-related death were similar between those two groups of patients (1.8% vs 1.7%, p = 0.8787) (Fig. 3). The outcomes in more detailed groups of renal insufficiency were presented in Supplementary Table S2.

We further used multivariable logistic regression to identify the risk factors for in-hospital bleeding among patients with renal insufficiency. Adjusted dose of LMWH presented as protective factor for in-hospital bleeding (OR 0.62, 95%CI 0.27–1.00, p = 0.0496) and the risk of bleeding increased as length of hospital stay prolonged (OR 1.03, 95%CI 1.01–1.06, p = 0.0014 (Table 2).