In our study, more than one fifth non-high risk acute PE patients were found to have renal insufficiency in admission. Among renal insufficient patients, LMWH was commonly applied and mostly with unadjusted dose. Adjusted dose of LMWH was significantly associated with lower rate of in-hospital bleeding for renal insufficient patients. To our knowledge, this is the first study focusing on the dosage of LMWH in PE patients with renal insufficiency and the association with in-hospital outcomes at real-world setting.

In our study, renal function was presented as creatinine clearance calculated by Cockcroft-Gault formula, this was mainly because that creatinine clearance is often used to the indication of kidney function for adjustment of dosage requirements, as our purpose on analysis of LMWH dosage. Present studies have reported a prevalence of renal insufficiency/dysfunction around 27%-49% in patients with acute PE [13]. In our study, 22.3% of involved normotensive acute PE patients were identified as renal insufficiency, lower than previous studies. The difference in the prevalence may due to the different equations in the estimation of renal insufficiency/dysfunction or the population involved.

We revealed a significantly increased risk of bleeding in patients with renal insufficiency during hospitalization. The rates of bleeding and major bleeding in CCr < 30 ml/min group with conventional dose of LMWH were comparable with previous real-world studies and meta-analysis. RIETE study reported the rates of major bleeding: 6.4% in CCr < 30 ml/min, fatal bleeding 1.0% during the first 15 days [14] and 8.3% bleeding events were found in a recent meta-analysis focused on the use of LMWH in VTE patients with severe renal insufficiency [15].

The 2019 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines of acute PE recommends UFH for patients with serious renal impairment (CCr ≤ 30 ml/min) and because that renal clearance is indirectly proportional to molecular weight, an adapted dosing scheme should be used while LMWH is prescribed in patients with CCr 15-30 ml/min [16]. Enoxaparin is the most commonly used LMWH and mostly studied, the 1-mg/kg QD regimen is recommended for severe CKD. There is no data for dalteparin and tinzaparin in severe CKD. For dosage adjustment purposes, it is recommended to monitor the activity of (anti-Xa level in order to avoid underdosage and achieve optimal therapeutic level, respectively. However, monitoring the activity of anti-Xa was not available in all healthcare providers, and dosing indications are results of either small-scale open-label studies, or analysis of CKD subgroups in randomized trials, adopted by guidelines, which, inevitably, are of low level of evidence [16]. In our study, a very high proportion of conventional dose LMWH was found in patients with renal insufficiency, including CCr < 30 ml/min.

Anticoagulation therapy among PE patients with renal insufficiency has been taken into consideration in recent real-world studies, The Global Anticoagulant Registry in the Field-Venous Thromboembolism (GARFILED-VTE) reported an up to 60% usage of parenteral therapy among VTE patients with moderate to severe CKD in the first month of treatment [17]. In RIETE study, the proportion of LMWH non-adherent management was as high as 20.8% for severe renal insufficiency, severe obesity and unstable PE patients and was related to high risk of death [7]. Another analysis of RIETE study found that most of the VTE patients with renal insufficiency received LMWH as initial therapy, with a mean daily dosage similar as the recommended dose for patients with normal renal function. Of note, the rates of major bleeding and fatal bleeding in patients with severe renal insufficiency were similar between those receiving UFH or LMWH, and no difference in mean LMWH doses was found between those patients who died and survived [18]. A newly developed risk score for predicting early major bleeding in acute PE had also identified renal dysfunction as one of the four core parameters [19]. Researchers inferred that dosage of anticoagulant might be a reason for patients with renal insufficiency to have higher risk of bleeding.

Limited evidence for anticoagulation for patients with renal insufficiency has been provided by RCTs, as severe renal impairment was among regular exclusion criteria for clinical trials. Renal Insufficiency Study (IRIS) compared full dose UFH and reduced dose of tinzaparin (175 IU/kg once daily) in renally impaired patients ≥ 70 years with acute DVT, the mortality favored UFH group and the rates of clinically relevant bleeding by day 90 were similar in the tinzaparin (11.9%) and UFH (11.9%) groups [20]. A post-hoc analysis of the CLOT study of cancer patients with renal impairment (CCr < 60 ml/min) showed that the bleeding rates were similar between dalteparin 200 IU/kg once daily and group and VKA [21]. A meta-analysis demonstrated that major bleeding increased when a standard therapeutic dose of enoxaparin was used (8.3% vs. 2.4%; odds ratio, 3.88 [CI, 1.78 to 8.45]) but may not increase when an empirically adjusted dose of enoxaparin is used (0.9% vs. 1.9%; OR 0.58 [CI, 0.09 to 3.78]) [15].

Our study innovatively analyzed the association between LMWH dosage and in-hospital outcomes for renal insufficient patients and a protective effect of adjusted dose LMWH for in-hospital bleeding events was demonstrated. The results emphasize the importance of LMWH dosage among renal insufficient patients, especially for safety regards. On the other hand, those who were administered adjusted dose of LMWH had significant higher rate of all-cause death during hospitalization. The reason would be that the complexity of background clinical status in renal insufficient patients leads to higher mortality or risk of fatal bleeding. This finding might alert physician to reduce the dosage of anticoagulant. Therefore, randomized clinical trials of larger sample of renal insufficient patients with longer follow-up time are required to investigate the relationship between treatment strategies and outcomes. We hypothesize that, for these patients, it is considerable to administer anticoagulants at a lower frequency or for a shorter time period. Dynamically monitor the risk of bleeding at follow-up period is also important.

Notably, our study found that the risk of bleeding increased as length of hospitalization prolonged. As the anticoagulation phase would last for at least 3 to 6 month, the prolonged hospitalization days means a longer observation time. Previous study reported an increasing risk of bleeding events after the first 15–30 days of anticoagulation in RIETE study, which was also proved by our study, indicating that the balance between efficacy and safety for those patients should be reassessed after acute phase of treatment [22].

There were a few limitations of our study: firstly, patients were not followed up during the study period and the long-term prognosis will be discussed in the following stages of CURES study, as described elsewhere [8]. Secondly, both products of LMWH regimen prescribed and dosage strengths in different hospitals varied (including enoxaparin sodium, dalteparin sodium, nadroparin calcium, etc.), thus the detail of particular regimen of LMWH was unavailable. The only way to make the result comparable was to re-estimate the LMWH dosage according to body weight in analysis. Thirdly, previous study reported evidence of recovery of renal injury during the spectrum of acute PE [23], which indicated a dynamic monitoring of creatinine is strongly required during follow-up period, to reassess prognosis (especially bleeding risk) and modify the dosage of drugs. In this study, our database only included the creatinine level at admission, so it was unavailable, so the recovery of renal function was unable to be observed. Fourthly, because DOACs were seldom administered during study period, the dosage and prognosis related to DOACs were not investigated in this study. However, even though DOACs are being widely prescribed as substitutes of traditional anticoagulants, LMWH still acts as the first-line drug for specific population, such as patients with cancer or pregnancy, according to ESC/ERS guidelines.

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