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Thromb Haemost 2025; 125(09): 821-824
DOI: 10.1055/a-2510-6370
Invited Clinical Focus

Heterogeneity in American and European Peripheral Artery Disease Guidelines on Non-statin Lipid-Lowering Therapy and Rivaroxaban

Mehrdad Zarghami
1   Department of Medicine, Jamaica Hospital Medical Center, Queens, New York, United States
2   Division of Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Sina Rashedi
3   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Gregory Piazza
2   Division of Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
3   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Marie Denise Gerhard-Herman
2   Division of Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Geoffrey D. Barnes 
4   Frankel Cardiovascular Center, University of Michigan Ann Arbor, Michigan, United States
,
Behnood Bikdeli
2   Division of Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
3   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
5   YNHH/Yale Center for Outcomes Research and Evaluation (CORE), New Haven, Connecticut, United States
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New guidelines of the American College of Cardiology and the American Heart Association (ACC/AHA)[1] and the European Society of Cardiology (ESC)[2] for peripheral artery disease (PAD) present comprehensive frameworks for management. Although both guidelines share thoughtful recommendations based on a review of randomized controlled trials (RCTs), noteworthy discrepancies exist regarding the recommended pharmacotherapies for PAD. We focus on two such areas: Adding non-statin lipid-lowering agents[3] [4] and incorporating low-dose rivaroxaban.[5] [6] [7] [8] We reflect on issues about the selection and interpretation of studies in these guidelines and the opportunity to improve aligning the recommendations with the current best evidence.

Non-statin Lipid-lowering Agents

Ezetimibe

The ACC/AHA guideline classifies ezetimibe as a class-2a recommendation (level of evidence [LOE]-B)[1] ([Fig. 1]). This recommendation acknowledges the reduction in major adverse cardiovascular events (MACE) but emphasizes the lack of evidence for PAD-specific outcomes, such as major adverse limb events (MALE).[1]

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Fig. 1 Comparison of guideline recommendations for non-statin lipid-lowering agents and rivaroxaban for peripheral arterial disease (PAD). Although the American College of Cardiology (ACC)/American Heart Association (AHA) and the European Society of Cardiology (ESC) guidelines are largely similar in their assessment criteria and reporting for level of evidence and class of recommendations, some differences exist in the class of recommendation and level of evidence definitions between the ACC/AHA and ESC guidelines for PAD.[1] [2] The ACC/AHA guideline classified a given treatment as class-1 when the benefit far outweighed the risk (benefit >>> risk),[1] while the ESC guideline provided class-1 recommendation when “evidence and/or general agreement indicated that a given treatment was beneficial, useful, or effective.”[2] The ACC/AHA guideline offered class-2a recommendation when the treatment was reasonable, could be useful, effective, or beneficial (benefit >> risk),[1] whereas the ESC guideline considered class-2a when “conflicting evidence and/or a divergence of opinion existed about the usefulness/efficacy of the given treatment and the weight of evidence/opinion was in favor of usefulness/efficacy.”[2] However, the overall methods of the two guidelines for clinical recommendations were similar, and both guidelines evaluated the same evidence base.[1] [2] The ACC/AHA guideline provides class-2a recommendations for adding ezetimibe or PCSK9 inhibitors to statin therapy and class-1 for adding low-dose rivaroxaban to aspirin in patients with PAD.[1] However, the ESC guideline endorses adding ezetimibe and PCSK9 inhibitors as class-1 recommendations and low-dose rivaroxaban as class-2a.[2] LDL-C, low-density lipoprotein-cholesterol; LOE, level of evidence; MACE, major adverse cardiovascular events; MALE, major adverse limb events; PCSK9, proprotein convertase subtilisin/kexin type 9; RCT, randomized controlled trial.

In contrast, the ESC guideline provides a class-1 (LOE-B) recommendation for adding ezetimibe when low-density lipoprotein cholesterol (LDL-C) target goals are not met with statins.[2] This stems from a sub-analysis of the IMPROVE-IT trial in patients with poly-vascular disease, showing a reduction in cardiovascular events with ezetimibe compared with placebo.[9] The guideline advocates using statins and ezetimibe before considering proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.[2]

The IMPROVE-IT trial enrolled 18,144 participants after acute coronary syndromes (ACS), of whom 1,005 (5.5%) had PAD.[9] This study demonstrated that the combination of ezetimibe plus moderate-intensity simvastatin compared with simvastatin monotherapy led to a significant reduction in a composite of cardiovascular death, coronary events, or non-fatal stroke (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.89–0.99).[9] Subgroup-specific results for patients with PAD were not reported. IMPROVE-IT trial did not evaluate ezetimibe as an add-on to high-intensity statin therapy, which is often used in PAD management.[10] Moreover, no PAD-specific outcome trials exist for ezetimibe.


 

PCSK9 Inhibitors

The ACC/AHA guideline classifies the recommendation for PCSK9 inhibitors (alirocumab and evolocumab) as class-2a (LOE-B).[1] The ACC/AHA guideline refers to subgroup analyses of two main outcome trials.[11] [12]

Conversely, the ESC guideline recommends PCSK9 inhibitors (alirocumab, evolocumab) as class-1 (LOE-A) when LDL-C targets are not achieved with statins plus ezetimibe.[2] The ESC guideline refers to the secondary analyses of main PCSK9 inhibitor outcome trials[11] [12] and a PAD-specific smaller RCT that suggested improved surrogate markers such as flow-mediated dilation and maximal walking time.[13]

In the FOURIER trial of 27,564 patients, evolocumab significantly reduced the risk of a composite of cardiovascular death, ACS, stroke, or coronary revascularization compared with placebo (HR 0.85, 95%CI 0.75–0.92).[14] These findings were consistent in the PAD subgroup, comprising 3,642 (13.2%) patients, in which evolocumab led to a reduction in MACE (HR 0.79, 95%CI 0.66–0.94) and a numeric reduction in MALE (HR 0.63, 95%CI 0.39–1.03).[11] The ODYSSEY OUTCOMES trial included 18,924 patients post-ACS.[12] Alirocumab reduced the risk of MACE (HR 0.83, 95%CI 0.74–0.94) overall. In the subgroup with PAD (n = 759, 4.0%), the risk reduction with alirocumab was directionally similar (HR 0.83, 95%CI 0.62–1.10), and there was a reduction in MALE (HR 0.59, 95%CI 0.40–0.86).[12] The Evol-PAD study involved 70 participants with PAD and claudication (35 receiving evolocumab and 35 receiving placebo), explored some functional and surrogate outcomes, and suggested a 37.7% improvement in mean walking time.[13] However, the study was not powered for cardiovascular or PAD-specific outcomes, including MALE.[13]


 

Rivaroxaban

The ACC/AHA guideline offers a class-1 recommendation (LOE-A) for low-dose rivaroxaban (2.5 mg twice daily) combined with aspirin for symptomatic patients with PAD, including those undergoing revascularization.[1] The guideline emphasizes the effectiveness of this combination in reducing MACE and MALE in patients with PAD, referring to the main analyses and sub-studies of two large RCTs.[15] [16]

In contrast, the ESC guideline provides a class-2a recommendation for the use of low-dose rivaroxaban in combination with aspirin for patients with PAD who are at high ischemic risk and non-high bleeding risk (LOE-A), as well as those with PAD and non-high bleeding risk following lower-limb revascularization (LOE-B).[2] While emphasizing the reduction in ischemic events, the guideline also notes the increased risk of bleeding with rivaroxaban.[2]

The COMPASS and VOYAGER-PAD trials are the two relevant RCTs.[15] [16] COMPASS enrolled 27,395 patients with ASCVD,[16] including 4,129 (15.1%) with lower extremity PAD,[17] while VOYAGER-PAD exclusively enrolled 6,564 patients with lower extremity PAD post-revascularization.[15] COMPASS demonstrated a significant reduction with rivaroxaban 2.5 mg twice daily plus aspirin, compared with aspirin alone in a composite of cardiovascular death, stroke, or MI (HR 0.76, 95%CI 0.66–0.86) and mortality (HR 0.82, 95%CI 0.71–0.96) but with an increase in the risk of major bleeding (HR 1.70, 95%CI 1.40–2.05).[16] In the subgroup of patients with PAD, the results were similar, showing a reduction in MACE (HR 0.71, 95%CI 0.53–0.97) and MALE (HR 0.55, 95%CI 0.34–0.88) and an increase in major bleeding (HR 1.71, 95%CI 1.06–2.77).[17] VOYAGER-PAD found a reduction in a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death (HR 0.85, 95%CI 0.76–0.96), and acute limb ischemia (HR 0.67, 95%CI 0.55–0.82) and an increase in the International Society on Thrombosis and Haemostasis major bleeding (HR 1.42, 95%CI 1.10–1.84) with rivaroxaban compared with placebo, in addition to aspirin.[15] Low-dose rivaroxaban plus aspirin compared with aspirin alone was associated with a reduced risk of net adverse clinical events of MACE, MALE, and fatal or critical organ bleeding in patients with symptomatic lower extremity PAD in the COMPASS trial (HR 0.75, 95% CI 0.58–0.96).[17] The findings for the net adverse clinical events from the VOYAGE-PAD trial should be evaluated in future investigations. Low-dose rivaroxaban plus aspirin compared with aspirin alone was associated with a reduced risk of net adverse clinical events of MACE, MALE, and fatal or critical organ bleeding in patients with symptomatic lower extremity PAD in the COMPASS trial (HR 0.75, 95% CI 0.58–0.96).[17] The findings for the net adverse clinical events from the VOYAGE-PAD trial should be evaluated in future investigations.


 

Harmonizing the Recommendations with Existing Evidence

Both guidelines were published in 2024 and evaluated a similar RCT evidence base. Despite similar criteria for evidence screening and assessment and a similar pool of studies, the ACC/AHA and ESC guidelines interpreted the balance of benefit/risk differently. The ESC guideline provides stronger recommendations for non-statin lipid-lowering therapies with limited evidence and endorses a class-2a recommendation for adding rivaroxaban in the PAD treatment, an intervention with more robust evidence, including a dedicated clinical trial in PAD. In clinical practice, treatment with ezetimibe or PCSK9 inhibitors can be considered for patients with PAD who either have inadequate LDL-C control despite maximally tolerated statin therapy or are statin-intolerant. This is particularly reasonable for patients with vascular disease in multiple vascular beds. However, PAD-specific RCTs are needed to confirm their efficacy in the subset with isolated PAD. The addition of low-dose rivaroxaban to aspirin should be considered for patients with PAD and a high risk of ischemia or thrombotic events who do not have a high risk of bleeding to minimize MALE and cardiovascular complications. Despite the guideline recommendations for dual pathway inhibition with antiplatelet therapy plus low-dose rivaroxaban in patients with PAD, its adoption in clinical practice remains limited.[18] This might be, at least in part, due to concerns for increased risk of bleeding events with this approach. The evolving landscape of PAD management necessitates careful consideration of the latest evidence to optimize patient care.[19] Discrepancies between the guidelines also underscore the need for additional high-quality research in patients with PAD. For instance, neither of the guidelines addressed possible ethnic–racial differences in atherothrombotic complications[20] and bleeding associated with antithrombotic therapy[21] [22] in patients with PAD. Until additional high-quality data emerge, harmonizing the guideline recommendations based on current best evidence can reduce confusion and improve the clarity of messaging to clinicians who are charged with navigating these nuances in shared decision-making with patients to improve outcomes.


 

 

 

Conflict of Interest

G.D.B. reports grants from Boston Scientific. He also reports consulting roles at Pfizer, Bristol-Myers Squibb, Janssen, Bayer, AstraZeneca, Sanofi, Anthos, Abbott Vascular, and Boston Scientific, as well as a Board of Directors role at Anticoagulation Forum. G.P. reports research grants from BMS/Pfizer, Janssen, Alexion, Bayer, Amgen, BSC, Esperion, 1R01HL164717–01. He also reports advisory roles at BSC, Amgen, BCRI, PERC, NAMSA, BMS, Janssen, and Regeneron. Outside the submitted work, B.B. is supported by a Career Development Award from the American Heart Association and VIVA Physicians (#938814). He was supported by the Scott Schoen and Nancy Adams IGNITE Award and is supported by the Mary Ann Tynan Research Scientist award from the Mary Horrigan Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital and the Heart and Vascular Center Junior Faculty Award from Brigham and Women's Hospital. He also reports that he was a consulting expert on behalf of the plaintiff for litigation related to two specific brand models of IVC filters. Dr. Bikdeli has not been involved in the litigation in 2022–2024, nor has he received any compensation in 2022–2024. He also reports that he is a member of the Medical Advisory Board for the North American Thrombosis Forum and serves in the Data Safety and Monitory Board of the NAIL-IT trial funded by the National Heart, Lung, and Blood Institute and Translational Sciences. He is also a collaborating consultant with the International Consulting Associates and the US Food and Drug Administration in a study to generate knowledge about the utilization, predictors, retrieval, and safety of IVC filters. He also receives compensation as an Associated Editor for the New England Journal of Medicine Journal Watch Cardiology, as an Associate Editor for Thrombosis Research, and as an Executive Associate Editor for JACC, and is a Section Editor for Thrombosis and Haemostasias (no compensation). Other authors report no disclosures.


Address for correspondence

Behnood Bikdeli, MD, MS
Division of Cardiovascular Medicine, Brigham and Women's Hospital
75 Francis Street, Boston, MA 02115
United States   

Publication History

Received: 14 November 2024

Accepted: 06 January 2025

Accepted Manuscript online:
07 January 2025

Article published online:
24 January 2025

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Zoom
Fig. 1 Comparison of guideline recommendations for non-statin lipid-lowering agents and rivaroxaban for peripheral arterial disease (PAD). Although the American College of Cardiology (ACC)/American Heart Association (AHA) and the European Society of Cardiology (ESC) guidelines are largely similar in their assessment criteria and reporting for level of evidence and class of recommendations, some differences exist in the class of recommendation and level of evidence definitions between the ACC/AHA and ESC guidelines for PAD.[1] [2] The ACC/AHA guideline classified a given treatment as class-1 when the benefit far outweighed the risk (benefit >>> risk),[1] while the ESC guideline provided class-1 recommendation when “evidence and/or general agreement indicated that a given treatment was beneficial, useful, or effective.”[2] The ACC/AHA guideline offered class-2a recommendation when the treatment was reasonable, could be useful, effective, or beneficial (benefit >> risk),[1] whereas the ESC guideline considered class-2a when “conflicting evidence and/or a divergence of opinion existed about the usefulness/efficacy of the given treatment and the weight of evidence/opinion was in favor of usefulness/efficacy.”[2] However, the overall methods of the two guidelines for clinical recommendations were similar, and both guidelines evaluated the same evidence base.[1] [2] The ACC/AHA guideline provides class-2a recommendations for adding ezetimibe or PCSK9 inhibitors to statin therapy and class-1 for adding low-dose rivaroxaban to aspirin in patients with PAD.[1] However, the ESC guideline endorses adding ezetimibe and PCSK9 inhibitors as class-1 recommendations and low-dose rivaroxaban as class-2a.[2] LDL-C, low-density lipoprotein-cholesterol; LOE, level of evidence; MACE, major adverse cardiovascular events; MALE, major adverse limb events; PCSK9, proprotein convertase subtilisin/kexin type 9; RCT, randomized controlled trial.