Abstract
This case-control study evaluates low-density lipoprotein cholesterol levels and bleeding risk during anticoagulation in patients with acute venous thromboembolism.
Introduction
Low-density lipoprotein cholesterol (LDL-C) levels are a well-established therapeutic target for cardiovascular risk reduction, but their role in hemostasis remains less understood.1,2 While previous studies3,4,5 suggest that aggressive LDL-C lowering may increase bleeding risk in patients with arterial disease, this association has not been explored in patients receiving anticoagulation for venous thromboembolism (VTE). We sought to evaluate LDL-C levels and bleeding risk during anticoagulation in patients with acute VTE.
Methods
We conducted a case-control analysis using data from the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry, a large multicenter, observational registry enrolling consecutive patients with objectively diagnosed VTE.6 The study was conducted in accordance with the declaration of Helsinki. Ethics committee approval was obtained from Comité de Ética de la Investigación del Hospital Universitario Germans Trias i Pujol (Badalona, Spain). All participants provided written informed consent. The study included patients from March 2009 to July 2024 who had available baseline LDL-C levels. Because measuring LDL-C is not routine, 75.6% of patients did not have available LDL-C values. Therefore, we checked for potential selection bias by comparing baseline characteristics of patients with and without LDL-C measurements and found no major differences among patients without LDL-C measurements (eTable in Supplement 1). Bleeding events during the first 90 days of anticoagulation were classified as major or nonmajor bleeding according to standard definitions. We reported standardized differences between patients in both subgroups. Standardized differences greater than 0.1 in absolute value were considered relevant. Multivariable Cox proportional hazards regression models, adjusted for competing risks using the Fine-Gray method, were used to assess LDL-C levels and bleeding outcomes. This study followed the STROBE reporting guideline. Data were analyzed using SPSS version 20 (IBM Corp). To identify comparisons of clinical relevance, we reported standardized differences between patients in both subgroups. A standardized difference greater than 0.1 in absolute value was considered relevant.
Results
Among 19 237 patients with available LDL-C levels, 2502 (13.0%) had LDL-C levels less than 70 mg/dL (to convert to mmol/L, multiply by 0.0259). Compared with those with LDL-C levels of 70 mg/dL or higher, these patients were older, more frequently male, and had a higher prevalence of hypertension, diabetes, prior arterial disease, anemia, and active cancer (Table 1). Compared with those with LDL-C levels of 70 mg/dL or higher, these patients were older (standardized difference, 0.228), more frequently male (standardized difference, 0.125), and had a higher prevalence of hypertension (standardized difference, 0.254), diabetes (standardized difference, 0.355), prior arterial disease (standardized difference, 0.144), anemia (standardized difference, 0.436), and active cancer (standardized difference, 0.159). During the first 90 days of anticoagulation, 743 patients (3.9%) experienced bleeding events: 294 major bleeding, 449 nonmajor bleeding, and 32 fatal bleeding cases (Table 2). Patients with LDL-C levels less than 70 mg/dL had an increased risk of overall bleeding (adjusted hazard ratio [AHR], 1.40; 95% CI, 1.16-1.69) and nonmajor bleeding (AHR, 1.49; 95% CI, 1.17-1.90), with hematomas being the most frequent bleeding site (AHR, 2.11; 95% CI, 1.49-2.98). The increased bleeding risk was observed early during anticoagulation and was independent of statin use.
Table 1. Baseline Characteristics of Patients According to LDL-C Levels.
| Characteristic | LDL-C level, No. (%) | Standardized difference | |
|---|---|---|---|
| <70 mg/dL (n = 2502) | ≥70 mg/dL (n = 16 735) | ||
| Demographic | |||
| Sex | |||
| Female | 1088 (43) | 8322 (49.7) | 0.125 |
| Male | 1414 (57) | 8413 (50.3) | 0.125 |
| Age, mean (SD), y | 69 (17) | 65 (17) | 0.228 |
| BMI, mean (SD) | 28 (6.0) | 29 (5.7) | 0.136 |
| Outpatients | 1540 (64) | 11 388 (70) | 0.137 |
| Initial VTE presentation | |||
| Pulmonary embolism | 1694 (68) | 10 179 (61) | 0.144 |
| Lower-limb DVT | 661 (26) | 5836 (35) | 0.184 |
| Upper-limb DVT | 147 (5.9) | 720 (4.3) | 0.072 |
| Comorbidities | |||
| Chronic lung disease | 332 (13) | 1698 (10) | 0.097 |
| Hypertension | 1516 (61) | 8045 (48) | 0.254 |
| Diabetes | 720 (29) | 2409 (14) | 0.355 |
| Prior myocardial infarction | 373 (15) | 989 (5.9) | 0.299 |
| Prior ischemic stroke | 263 (11) | 965 (5.8) | 0.174 |
| Peripheral artery disease | 159 (6.4) | 550 (3.3) | 0.144 |
| Recent major bleeding | 98 (3.9) | 322 (1.9) | 0.119 |
| Serum lipid levels | |||
| Total cholesterol | 125 (27) | 189 (39) | 1.886 |
| LDL-cholesterol | 58 (8.1) | 118 (32) | 2.540 |
| HDL-cholesterol | 44 (22) | 46 (15) | 0.090 |
| Triglycerides | 128 (73) | 137 (65) | 0.134 |
| Risk factors for bleeding | |||
| Active cancer | 399 (16) | 1767 (11) | 0.159 |
| Liver cirrhosis | 27 (1.1) | 49 (0.3) | 0.095 |
| Gastroduodenal ulcer | 44 (1.8) | 163 (1.0) | 0.068 |
| Anemia | 1146 (46) | 4247 (25) | 0.436 |
| Leukocyte count >11 000/μL | 801 (32) | 4146 (25) | 0.161 |
| Platelet count <100 000/μL | 83 (3.3) | 286 (1.7) | 0.103 |
| Abnormal prothrombin time | 369 (16) | 1068 (7.0) | 0.294 |
| CrCl levels <60 mL/min | 1052 (42) | 4804 (29) | 0.282 |
| Prognostic scores for bleeding | |||
| RIETE, high-risk (≥4 points) | 439 (18) | 1191 (7.6) | 0.320 |
| VTE-BLEED, high-risk (≥2 points) | 1553 (63) | 7306 (45) | 0.371 |
| Modified ACCP, high-risk (≥2 points) | 1641 (71) | 7856 (50) | 0.436 |
| DOAC, high-risk (≥8 points) | 338 (19) | 1080 (9.0) | 0.287 |
Abbreviations: ACCP, American College of Chest Physicians; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CrCl, creatinine clearance; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; HDL, high-density lipoprotein: LDL, low-density lipoprotein: RIETE, Registro Informatizado Enfermedad TromboEmbólica; VTE-BLEED, venous thromboembolism-bleedings.
SI conversion factors: To convert CrCl level to milliliters per second per meter squared, multiply by 0.0167; HDL and LDL from mg/dL to mmol/L, multiply by 0.0259; platelets to ×109/L, multiply by 1; triglycerides from mg/dL to mmol/L, multiply by 0.0113; and WBCs to cells ×109/L, multiply by 0.001.
Table 2. Rates of Events During the First 90 Days According to LDL-C Levels at Baseline.
| Event | LDL-C level, No. (%) | Odds ratio (95%CI) | |
|---|---|---|---|
| <70 mg/dL (n = 2502) | ≥70 mg/dL (n = 16 735) | ||
| Overall bleeding | 158 (6.31) | 585 (3.50) | 1.86 (1.55-2.23) |
| Major bleeding | 62 (2.48) | 232 (1.39) | 1.81 (1.36-2.40) |
| Gastrointestinal | 16 (0.64) | 75 (0.45) | 1.43 (0.83-2.46) |
| Hematoma | 23 (0.92) | 53 (0.32) | 2.92 (1.79-4.77) |
| Intracranial | 11 (0.44) | 39 (0.23) | 1.89 (0.97-3.70) |
| Retroperitoneal | 5 (0.20) | 20 (0.12) | 1.67 (0.63-4.46) |
| Urinary | 2 (0.08) | 12 (0.07) | 1.11 (0.25-4.98) |
| Uterine | 1 (0.04) | 11 (0.07) | 0.61 (0.08-4.71) |
| Other sites | 4 (0.16) | 22 (0.13) | 1.22 (0.42-3.53) |
| Nonmajor bleeding | 96 (3.84) | 353 (2.11) | 1.85 (1.47-2.33) |
| Hematoma | 24 (0.96) | 76 (0.45) | 2.12 (1.34-3.37) |
| Urinary | 18 (0.72) | 91 (0.54) | 1.33 (0.80-2.20) |
| Gastrointestinal | 23 (0.92) | 70 (0.42) | 2.21 (1.38-3.54) |
| Uterine | 4 (0.16) | 20 (0.12) | 1.34 (0.46-3.92) |
| Other sites | 27 (1.08) | 96 (0.57) | 1.89 (1.23-2.90) |
| Fatal bleeding | 11 (0.44) | 21 (0.13) | 3.51 (1.69-7.30) |
| Intracranial | 4 (0.16) | 10 (0.06) | 2.68 (0.84-8.55) |
| Retroperitoneal | 2 (0.08) | 5 (0.03) | 2.68 (0.52-13.8) |
| Gastrointestinal | 2 (0.08) | 3 (0.02) | 4.46 (0.75-26.7) |
| Hematoma | 1 (0.04) | 0 | NA |
| Other sites | 2 (0.08) | 3 (0.02) | 4.46 (0.75-26.7) |
| Nonbleeding deaths | 180 (7.2) | 533 (3.2) | 2.36 (1.98-2.81) |
| Pulmonary embolism | 10 (0.40) | 31 (0.19) | 2.16 (1.06-4.42) |
| Disseminated cancer | 48 (1.9) | 190 (1.1) | 1.70 (1.24-2.34) |
| Infection | 22 (0.88) | 48 (0.29) | 3.08 (1.86-5.12) |
| Heart failure | 17 (0.68) | 30 (0.18) | 3.81 (2.10-6.92) |
| Respiratory failure | 11 (0.44) | 49 (0.29) | 1.50 (0.78-2.90) |
| Multiorganic failure | 18 (0.72) | 48 (0.29) | 2.52 (1.46-4.34) |
| Bronchoaspiration | 10 (0.40) | 10 (0.06) | 6.71 (2.79-16.1) |
| Unknown | 16 (0.64) | 42 (0.25) | 2.56 (1.44-4.56) |
| Other | 28 (1.1) | 85 (0.51) | 2.22 (1.44-3.41) |
Abbreviations: LDL-C, low-density lipoprotein cholesterol; NA, not applicable.
SI conversion factors: To convert LDL from mg/dL to mmol/L, multiply by 0.0259.
Discussion
Study limitations include the high proportion of missing LDL-C data due to the lack of routine lipid testing. However, the lack of important baseline differences between included and excluded patients is notable. Additionally, our multivariable analysis confirmed that the association between LDL-C levels and bleeding risk was independent of these variables. Another limitation is the inability to account for LDL-C fluctuations over time, which may have affected bleeding risk, particularly in patients undergoing lipid-lowering therapy adjustments.
In this study, low LDL-C levels were associated with an increased risk of bleeding, particularly hematomas, in patients receiving anticoagulation for VTE. Given that LDL-C is not currently considered in bleeding risk stratification, our findings suggest a potential new factor for risk assessment in this population. Future studies should explore whether LDL-C levels can refine existing bleeding risk models and whether strategies to mitigate this risk are warranted.
eTable. Baseline Characteristics in Patients With- Versus Without Information on LDL-C Levels
Nonauthor Collaborators. The RIETE Investigators
Data Sharing Statement
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Associated Data
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Supplementary Materials
eTable. Baseline Characteristics in Patients With- Versus Without Information on LDL-C Levels
Nonauthor Collaborators. The RIETE Investigators
Data Sharing Statement
