Clinical insights on best medical therapy for peripheral artery disease

Patients with lower extremity peripheral artery disease (PAD) are at high risk for major adverse cardiovascular events (MACE), major adverse limb events (MALE), mortality, and future major lower extremity amputation (LEA). PAD patients with multivessel disease or relevant comorbidities such as diabetes and kidney failure are at an even higher risks for such events. [Lancet 2018;391:219-229] 

“According to the latest Organisation for Economic Cooperation and Development (OECD) report, LEA rates in Singapore are one of the highest in the world (2-3 times higher than in the UK), with four LEA episodes daily. The typical Asian PAD patients in Singapore are distinct from those of western populations. They are predominantly diabetic (90% vs 50%), with younger age at onset (50 vs 60 years), have minimal claudication symptoms, comprise mainly of below-knee athero-occlusive disease (vs aortoiliac-femoral thrombotic disease), and higher chronic renal failure rate (50% vs 27%). The key aim of the Ministry of Health’s ‘War on Diabetes’ is to reduce macrovascular complications of diabetes, including PAD. The high LEA rates indicate that either our revascularization policy and/or our current medical management of PAD are not optimal,” said Associate Professor Tjun Tang, Director of Research, SingHealth Duke-NUS Vascular Centre and Senior Consultant, Department of Vascular Surgery, Singapore General Hospital. 

A/Prof Tang is currently co-chair of the Vascular Medical Management Workgroup (VMW), with Dr Julian Wong, Director of Vascular Lab, National University Hospital and Senior Consultant, Department of Cardiac, Thoracic and Vascular Surgery, National University Heart Centre, Singapore. The objective of the VMW is to achieve a consensus among various specialties (vascular specialists, cardiologists, and endocrinologists) on the optimal medical management of PAD in Singapore. 

The VMW recognized the lack of guideline recommendations for the medical management of PAD, with current best practices referenced from cardiology studies. As such, they reviewed two landmark trials, COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) and VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD), and discussed the clinical applicability of the results in Singapore.

The COMPASS trial
The COMPASS trial was a multicentre, double-blind, randomized, placebo-controlled trial to evaluate anticoagulation strategies with rivaroxaban among patients with stable atherosclerosis. Among the 27,395 participants enrolled, 7,470 had PAD. In those with PAD, rivaroxaban 2.5 mg given twice daily, combined with aspirin 100 mg once daily, significantly reduced the risk of MACE (composite endpoint of cardiovascular death, myocardial infarction, or stroke), MALE (the development of acute or chronic limb ischaemia, including any additional major amputations due to a vascular event), vascular and major amputations vs aspirin alone (Table 1). [N Engl J Med 2017;377:1319-1330; Lancet 2018;391:219-229] 

According to the VMW report, the divergence of the MACE (Figure 1a) and MALE (Figure 1b) graphs showed a difference in relative risk reduction between patients on aspirin vs rivaroxaban 2.5 mg BID plus aspirin. As the curves showed a divergence at 1 year into the treatment, it means patients should ideally be on a low-dose rivaroxaban plus aspirin for at least 2–3 years to obtain a significant positive outcome. 

“In the COMPASS trial, most patients came back for re-intervention within the first year. Hence, intervention with better treatment options should be introduced at that point because most patients in local practice present with chronic limb-threatening ischaemia (CLTI),” said Dr Wong. 

Patients on low-dose rivaroxaban plus aspirin also had lower incidence rates of acute limb ischaemia (ALI), critical limb ischaemia (CLI), and major amputations than those on aspirin alone. While the use of rivaroxaban and aspirin combination increased major bleeding (3% vs 2%, hazard ratio [HR], 1.61; p=0.0089) vs aspirin alone, there was no excess in fatal bleeding, intracranial bleeding, or bleeding into critical organs.

VOYAGER PAD
The VOYAGER PAD study affirmed these findings, specifically in the post-revascularization PAD patients. Rivaroxaban 2.5 mg BID plus aspirin significantly reduced the composite primary endpoint (MI, stroke, or CV) vs aspirin alone (p=0.009) (Figure 2). This reduction in the composite primary endpoint was heavily influenced by the reduction in ALI. 

In terms of safety, major bleeding as defined by Thrombolysis in Myocardial Infarction (TIMI) classification was not significantly different between rivaroxaban plus aspirin and aspirin alone (2.65% vs 1.87%; p=0.07). There was also no significant difference in fatal bleeding, intracranial haemorrhage, and critical organ bleeding. [N Engl J Med 2020;382:1994-2004]

Application of results to Singapore practice
“Both the COMPASS and VOYAGER trials involved mainly Caucasians; Asians made up only about 15% of the participants. Many of them presented with claudication and symptomatic PAD, whereas in local practice, most patients present late with a significant amount of tissue loss and CLTI. Hence, more local studies and local data collection are needed to investigate how the current trial results may affect Singapore patients, particularly those at higher risk, including those with bad ischaemic heart disease, chronic renal impairment, and end-stage renal failure,” said A/Prof Tang. 

“The VMW discussions also revealed there was a low awareness among physicians and patients in Singapore of this new regimen. Many vascular specialists are not comfortable in medically managing post-revascularization PAD patients due to the perceived bleeding risk. However, bleeding rates for rivaroxaban 2.5 mg BID plus low-dose aspirin in COMPASS and VOYAGER PAD trials were comparable to rivaroxaban higher dose (15 or 20 mg). The fatal bleeding rate is also very low. Physicians should consider the long-term benefit and protection from this regimen, such as prevention of MACE and MALE, and weigh it against the cost of the drug and the accumulative bleeding risk,” said Dr Wong. 

Both experts are currently using rivaroxaban plus aspirin in their CLTI patients following lower limb revascularization, who are one of the most challenging group to treat in the community.

Key points
●            In patients with PAD, low-dose rivaroxaban taken twice daily plus aspirin once daily reduces major adverse cardiovascular and limb events vs aspirin alone.
●            Fatal or critical organ bleeding was not increased with this combination regimen.
●            More local data should be collected to ascertain how these findings can be applied to Singapore.