Highlight
Bempedoic acid was associated with a 42% relative reduction in first venous thromboembolism event compared with placebo in a post hoc analysis of the CLEAR Outcomes randomized clinical trial.
The signal was directionally consistent for both deep vein thrombosis and pulmonary embolism, with hazard ratios of 0.56 and 0.61, respectively.
These findings extend interest in lipid-lowering therapy beyond atherosclerotic risk reduction and raise the possibility that ATP citrate lyase inhibition may influence thrombotic biology, although the analysis remains exploratory.
The results are clinically relevant because the trial enrolled statin-intolerant patients, a population with persistently high residual cardiovascular risk and limited options for broad cardiometabolic risk modification.
Background
Venous thromboembolism, comprising deep vein thrombosis and pulmonary embolism, remains a major source of preventable morbidity and mortality worldwide. VTE is associated with hospitalization, cancer, surgery, immobilization, advancing age, chronic inflammatory states, and cardiometabolic disease. Even after the acute event, recurrent thrombosis, chronic thromboembolic pulmonary hypertension, and post-thrombotic syndrome can produce durable health and economic burdens.
Interest in the relationship between lipid-lowering therapy and VTE has grown over the last two decades. Statins have repeatedly shown signals for lower VTE risk in randomized and observational datasets, although effect size and consistency vary by population and study design. More recently, monoclonal antibody PCSK9 inhibitors have also been associated with reduced VTE risk in secondary analyses. These observations suggest that pathways linked to lipoprotein metabolism, inflammation, endothelial function, and coagulation may intersect more than previously appreciated.
Bempedoic acid is an oral ATP citrate lyase inhibitor that lowers low-density lipoprotein cholesterol upstream from HMG-CoA reductase. Because it is activated primarily in the liver and not in skeletal muscle, it has become an important option for patients with statin intolerance. The parent CLEAR Outcomes trial demonstrated cardiovascular benefit in this high-risk population. Whether bempedoic acid also affects venous thrombosis risk had not been established before this report.
Study Design
This investigation was a post hoc analysis of CLEAR Outcomes, a randomized, double-blind, placebo-controlled cardiovascular outcomes trial. Participants were enrolled between December 22, 2016, and August 14, 2019, at 1250 centers across 32 countries. Statistical analysis for the present report was conducted between March 10, 2025, and February 19, 2026.
The trial enrolled statin-intolerant adults aged 18 to 85 years who were at high risk for or had established atherosclerotic cardiovascular disease. A total of 13,970 participants were randomized: 6,992 to oral bempedoic acid 180 mg daily and 6,978 to placebo. The mean age was 65.5 years, 48.2% were female, 2.0% had a history of VTE at baseline, and 8.7% were receiving systemic anticoagulation at randomization.
The primary outcome for this post hoc analysis was time to first VTE event, defined as a composite of deep vein thrombosis or pulmonary embolism. The individual components were also examined separately. Median follow-up was 40.6 months, with an interquartile range of 37.1 to 46.2 months.
Because this was a post hoc analysis rather than a prespecified primary efficacy end point, the findings should be interpreted as hypothesis-generating despite the randomized framework and blinded adjudication context of the parent trial.
Key Results
Overall VTE risk
A total of 106 VTE events occurred during follow-up. Of these, 39 occurred in the bempedoic acid group and 67 in the placebo group. This translated to a hazard ratio of 0.58 with a 95% confidence interval of 0.39 to 0.86 and a P value of .006.
For clinicians, that estimate suggests a clinically meaningful reduction in relative risk. The absolute event rate was low, as expected in a broad cardiovascular outcomes population rather than a cohort enriched for recent thrombosis, but the separation between groups is notable given that most patients were not selected on the basis of prior VTE.
Deep vein thrombosis
For deep vein thrombosis specifically, the hazard ratio was 0.56 with a 95% confidence interval of 0.31 to 0.996 and a P value of .045. This result is statistically significant but borderline, with the upper confidence interval limit nearly crossing 1.0. The point estimate nevertheless aligns with the overall VTE finding.
Pulmonary embolism
For pulmonary embolism, the hazard ratio was 0.61 with a 95% confidence interval of 0.37 to 0.996 and a P value of .046. As with deep vein thrombosis, the estimate is consistent in direction and magnitude with the composite outcome, though the confidence interval again sits close to the threshold for null effect.
Clinical interpretation of effect size
The composite signal is more robust than either component alone, which is not surprising given the limited number of events. The numerical consistency across DVT and PE adds credibility to the observation, but the modest event count also means that replication is important before these data influence thrombosis-specific treatment decisions.
One of the more interesting features of the dataset is that the VTE reduction emerged in a population defined by statin intolerance and elevated cardiovascular risk. These patients often have overlapping metabolic and inflammatory risk factors that may predispose to both arterial and venous disease. If the association is causal, bempedoic acid may offer a dual vascular benefit in selected patients who cannot tolerate statins.
Mechanistic Considerations
The study was not designed to establish mechanism, but several biologically plausible pathways deserve consideration. Bempedoic acid inhibits ATP citrate lyase, a key enzyme linking carbohydrate metabolism to cholesterol and fatty acid synthesis. This lowers LDL cholesterol and may also influence inflammatory signaling. In prior work, bempedoic acid has been associated with reductions in high-sensitivity C-reactive protein, suggesting anti-inflammatory effects beyond lipid lowering.
Inflammation contributes to venous thrombosis through endothelial activation, leukocyte recruitment, tissue factor expression, platelet-leukocyte interactions, and impaired fibrinolysis. Therapies that lower inflammatory tone may therefore reduce thrombotic susceptibility even when they are developed primarily for atherosclerotic prevention.
Another possibility is that lipid-lowering itself alters thrombosis biology. Lipoproteins may affect coagulation factor expression, endothelial function, and blood viscosity. Prior VTE signals with statins and PCSK9 inhibitors support the concept that some lipid-lowering strategies can modify venous as well as arterial event risk. Whether ATP citrate lyase inhibition exerts a class-specific effect or simply shares downstream biology with other LDL-lowering agents remains uncertain.
It is also possible that the observed association reflects a broader cardiometabolic benefit not fully reducible to LDL cholesterol alone. Without mediation analyses or dedicated biomarker studies, causal inference at the mechanistic level remains limited.
Strengths of the Analysis
The most important strength is that the dataset comes from a large randomized, double-blind, placebo-controlled trial with international enrollment and prolonged follow-up. Randomization reduces confounding that commonly complicates observational VTE research. The cohort size, nearly 14,000 participants, is substantial for a secondary thrombosis analysis in a cardiovascular trial.
The study population is also clinically important. Statin-intolerant patients remain undertreated and are frequently encountered in both preventive cardiology and general internal medicine. Demonstrating additional vascular benefit in this group has practical implications because oral therapies are often preferred and easier to scale than injectable alternatives.
Finally, the consistency of the direction of effect across the composite endpoint and its individual components supports internal coherence, even if event counts were limited.
Limitations and Cautions
The main limitation is that this was a post hoc analysis. The trial was not primarily designed or powered for VTE outcomes, and multiplicity issues must be considered when interpreting nominal P values. Even significant findings in secondary analyses require validation.
The absolute number of events was modest, especially for the individual DVT and PE endpoints. This is reflected in the confidence intervals, which approach 1.0 for both component outcomes. A few events in either direction could materially shift the results.
The report summary does not provide detailed subgroup analyses, event adjudication nuances, competing risk analyses, or time-varying information regarding anticoagulation changes after randomization. Baseline systemic anticoagulation was present in 8.7% of participants, and although randomization should balance this factor, more granular thrombosis-risk stratification would help contextualize the results.
Generalizability is another consideration. CLEAR Outcomes enrolled statin-intolerant patients at high cardiovascular risk or with established atherosclerotic cardiovascular disease. These findings may not automatically extend to lower-risk populations, patients with active cancer, those with recent surgery or trauma, or individuals with strong inherited thrombophilia.
Most importantly, the study does not justify using bempedoic acid as a substitute for evidence-based VTE prophylaxis or anticoagulation. Patients with established indications for thromboprophylaxis should continue guideline-directed care.
How This Fits With Existing Evidence
The findings are directionally aligned with prior literature suggesting that some lipid-lowering therapies may reduce VTE risk. The JUPITER trial previously reported lower VTE incidence with rosuvastatin in apparently healthy adults with elevated high-sensitivity C-reactive protein. Meta-analyses of statin trials and observational studies have generally supported a modest protective association, though not universally. More recently, analyses from PCSK9 inhibitor trials suggested a reduction in VTE, reinforcing the concept that lipoprotein-related pathways may influence venous thrombosis.
Against that backdrop, the current study broadens the discussion to ATP citrate lyase inhibition. If confirmed, the clinical message would be that several non-anticoagulant cardiovascular therapies may have beneficial spillover effects on venous thrombotic events. Still, the hierarchy of evidence matters: post hoc analyses can identify promising signals, but dedicated confirmation is needed before practice paradigms change.
Implications for Clinical Practice
For current practice, the most immediate implication is not that clinicians should prescribe bempedoic acid for VTE prevention. Rather, when selecting lipid-lowering therapy for a statin-intolerant patient with high cardiovascular risk, these data offer an additional potentially favorable consideration. The established indication remains LDL cholesterol reduction and cardiovascular event prevention.
In patients who have overlapping arterial and venous risk concerns, the results may modestly strengthen the rationale for choosing bempedoic acid when otherwise appropriate. However, treatment decisions should still be grounded in total cardiovascular risk, degree of LDL lowering needed, tolerability, kidney and liver considerations, cost, availability, and use of other agents such as ezetimibe or PCSK9-targeted therapy.
Clinicians should also remember that bempedoic acid has a known safety profile that includes increased uric acid, gout, and small increases in some adverse events in prior studies. This VTE analysis does not replace a balanced assessment of benefits and harms for the individual patient.
Research Directions
Several next steps follow from this analysis. First, replication in independent randomized datasets would be valuable, including pooled analyses across bempedoic acid trials. Second, mechanistic studies should examine whether VTE reduction tracks more closely with LDL lowering, C-reactive protein reduction, or other biomarkers of coagulation and endothelial activation.
Third, subgroup analyses could help determine whether the signal is stronger in patients with prior VTE, obesity, diabetes, chronic kidney disease, inflammatory disorders, or concomitant antithrombotic therapy. Fourth, formal mediation models may clarify whether the apparent benefit is independent of background lipid changes.
Finally, if the signal remains consistent, future prospective studies could consider VTE as a prespecified endpoint in high-risk cardiometabolic populations.
Conclusion
This post hoc analysis of the CLEAR Outcomes trial suggests that bempedoic acid may reduce the risk of venous thromboembolism in statin-intolerant patients at high risk for or with established cardiovascular disease. The reduction was significant for the composite VTE endpoint and directionally consistent for both deep vein thrombosis and pulmonary embolism.
The findings are clinically intriguing because they extend the vascular profile of bempedoic acid beyond atherosclerotic event reduction and align with earlier observations seen with statins and PCSK9 inhibitors. At the same time, the analysis remains exploratory, with limited event numbers and the inherent constraints of post hoc inference. For now, bempedoic acid should be viewed as a lipid-lowering therapy with a promising thrombosis signal rather than as an established VTE-prevention drug. Confirmation in future studies will determine whether this observation becomes a meaningful part of routine risk-reduction strategy.
Funding and Trial Registration
Trial registration: ClinicalTrials.gov Identifier NCT02993406.
The present summary is based on the published report and abstracted trial information. Readers should consult the full article for detailed funding disclosures and author conflict-of-interest statements.
References
Spiazzi BF, Brennan D, Zingano CP, Powell HA, Nicholls SJ, Nissen SE, Laffin LJ. Bempedoic Acid and Venous Thromboembolism Risk Among Statin-Intolerant Patients: A Post Hoc Analysis of the CLEAR Outcomes Randomized Clinical Trial. JAMA Cardiology. 2026 May 27. PMID: 42201706.
Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. New England Journal of Medicine. 2023;388(15):1353-1364. PMID: 36876740.
Glynn RJ, Danielson E, Fonseca FAH, et al. A Randomized Trial of Rosuvastatin in the Prevention of Venous Thromboembolism. New England Journal of Medicine. 2009;360(18):1851-1861. PMID: 19329822.
Marston NA, Gurmu Y, Melloni GEM, et al. Association Between PCSK9 Inhibitor Therapy and Risk of Venous Thromboembolism. Circulation. 2020;141(20):1600-1607. PMID: 32167856.
