Patients with chronic PAD – What can be done to reduce the risk of cardiovascular and limb events?

Patient case

Despite her age of 68 years, Beatrice still had an active social life and enjoyed taking short walks to visit her friends who lived close by for a cup of tea and cake
Over the past year, she started experiencing pain in her legs while walking, which caused her to go out less often
Beatrice was reluctant to seek medical attention, but one of her friends insisted on taking her to visit the physician
A low ankle–brachial index (ABI) measurement and diagnostic imaging revealed that Beatrice has chronic peripheral artery disease (PAD) in her right leg. While screening for other cardiovascular risk factors, her physician found that she also has type 2 diabetes
Beatrice was told that she has a high risk of cardiovascular events such as stroke, heart attack and limb loss. Her physician advised her to continue her current lipid-lowering and antihypertensive therapies and to follow a healthy lifestyle
She left the clinic with prescriptions for antidiabetic medication and low‑dose aspirin

Beatrice is now taking several steps to reduce her cardiovascular risk, but she is still worried about losing her leg or having a stroke. Is there more that can be done to protect Beatrice from major adverse cardiovascular and limb events?

The consequences of PAD can be severe

Like Beatrice, many patients with PAD experience intermittent claudication or other leg symptoms.1 Co-morbid diabetes is also common in patients with PAD, and is estimated to occur in about 30–40% of patients.2,3 In fact, having diabetes approximately doubles the risk of developing PAD.4

Guidelines recommend a comprehensive risk factor management strategy that includes a healthy lifestyle and single antiplatelet therapy in all patients with symptomatic PAD, as well as statins, antihypertensive drugs and antidiabetic drugs where necessary.5,6

Beatrice and her physician are already following this advice, but is that enough to reduce her risk of major adverse cardiovascular and limb events?

Even patients with PAD who receive a high standard of risk factor management are at risk of major adverse cardiovascular and limb events, particularly when they also have diabetes. For example, one study estimated that patients who have PAD and diabetes, like Beatrice, have an approximately 1.5-fold increase in the risk of major cardiovascular events compared with those who only have PAD (hazard ratio [HR]=1.431; 95% confidence interval [CI] 1.276–1.605). The risk of major amputation was almost doubled in patients with PAD and co-morbid diabetes versus those with PAD alone (HR=1.863; 95% CI 1.372–2.531).7

Co-morbid diabetes is common in patients with PAD and increases the risk of cardiovascular and limb events2,3,7

Dual pathway inhibition (DPI) can offer increased vascular protection for patients with PAD

A sub-analysis of patients with chronic PAD in the COMPASS trial showed that DPI with rivaroxaban vascular dose 2.5 mg twice daily (bid) plus low-dose aspirin significantly reduced the risk of major adverse cardiovascular events (MACE; cardiovascular death, stroke or myocardial infarction) by 28%, the risk of major adverse limb events (MALE) including major amputation by 46% and the risk of major amputation by 70% compared with aspirin alone. The reduction in the risk of the combined outcome of MACE and MALE including major amputation was consistent between subgroups of patients with and without diabetes. The risk of major bleeding based on a modified definition of the International Society on Thrombosis and Haemostasis (ISTH) criteria was significantly increased in patients with PAD receiving DPI compared with patients receiving aspirin alone; however, the risk of fatal or intracranial haemorrhage was not significantly different between treatment arms.8

Most patients in COMPASS received guideline-recommended therapies for the prevention of cardiovascular events. Therefore, the benefits of DPI versus aspirin alone were observed in addition to the standard cardiovascular risk management strategies.8

Although DPI reduced the risk of MACE and MALE versus aspirin alone in all patient subgroups in COMPASS, those with co-morbidities such as diabetes were shown to benefit particularly from DPI versus aspirin alone. These patients had a higher absolute risk of cardiovascular and limb events compared with patients without co-morbid diabetes. Therefore, patients with co-morbid diabetes had a particularly favourable benefit–risk profile with DPI versus aspirin alone.9,10

Dual pathway inhibition can reduce the risk of major adverse cardiovascular and limb events in patients with chronic PAD in the presence and absence of co-morbid diabetes8

Because of the potential of DPI to prevent serious atherothrombotic events, the 2019 European Society of Vascular Medicine (ESVM) guidelines on PAD recommended considering DPI in patients with PAD without a high risk of bleeding as part of an overall vascular protection strategy.5 The 2019 European Society of Cardiology (ESC) guidelines on diabetes, pre-diabetes and cardiovascular diseases also recommended considering DPI in patients like Beatrice who have chronic symptomatic lower-extremity PAD and comorbid diabetes, and without a high risk of bleeding.6

Summary

Rivaroxaban vascular dose 2.5 mg bid plus low-dose aspirin is a new treatment option that has been shown to reduce the risk of major adverse cardiovascular and limb events in patients with PAD. What could antithrombotic protection using DPI mean for patients like Beatrice? It could mean enhanced protection against potentially debilitating cardiovascular events and less fear about the possibility of a life-changing limb event such as an amputation. As Professor Sonia Anand explains in the video below,

“by showing that we can reduce both MACE or MALE events by 31%, patients with PAD stand to benefit significantly with this new therapy.”

High-risk subgroups in COMPASS, CAD Patients with PAD
Sonja Anand on Treatment Strategies

References

Dhaliwal G, Mukherjee D. Peripheral arterial disease: epidemiology, natural history, diagnosis and treatment. Int J Angiol 2007;16:36–44. Return to content
Steg PG, Bhatt DL, Wilson PW et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297:1197–1206. Return to content
Smolderen KG, Gosch K, Patel M et al. PORTRAIT (patient-centered outcomes related to treatment practices in peripheral arterial disease: investigating trajectories): overview of design and rationale of an international prospective peripheral arterial disease study. Circ Cardiovasc Qual Outcomes 2018;11:e003860 Return to content
Song P, Rudan D, Zhu Y et al. Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Glob Health 2019;7:e1020–e1030. Return to content
Frank U, Nikol S, Belch J. et al. ESVM Guideline on peripheral arterial disease. Vasa 2019;48:27–34. Return to content
Cosentino F, Grant PJ, Aboyans V et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323. Return to content
Low Wang CC, Blomster JI, Heizer G et al. Cardiovascular and limb outcomes in patients with diabetes and peripheral artery disease: the EUCLID trial. J Am Coll Cardiol 2018;72:3274–3284. Return to content
Anand SS, Bosch J, Eikelboom JW et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:219–229. Return to content
Anand SS, Eikelboom JW, Dyal L, et al. Rivaroxaban Plus Aspirin Versus Aspirin in Relation to Vascular Risk in the COMPASS Trial. J Am Coll Cardiol. 2019;73(25):3271-3280. Anand SS, Eikelboom JW, Dyal L, et al. Rivaroxaban Plus Aspirin Versus Aspirin in Relation to Vascular Risk in the COMPASS Trial. J Am Coll Cardiol. 2019;73(25):3271-3280. Return to content
Bhatt DL, Eikelboom JW, Connolly SJ et al. The role of combination antiplatelet and anticoagulation therapy in diabetes and cardiovascular disease: insights from the COMPASS trial. Circulation 2020: doi:10.1161/CIRCULATIONAHA.120.046448. Return to content

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Updated date 10/10/2022

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Vascular Adviser