Commentary: Joint statement from the European Atherosclerosis Society and European Society of Vascular Medicine focuses on patients with peripheral arterial disease
Peripheral arterial disease (PAD) is one of the three leading cardiovascular diseases globally, together with coronary heart disease and cerebrovascular disease. Recent estimates show that PAD affects over 235 million people worldwide , with almost three quarters asymptomatic . Prevalence increases with age, with more than one in five people older than 60 years affected . As populations age, PAD will become more common, posing an increasing burden of disease. Increasingly this burden will be in lower and middle-income countries, aligned with smoking and diabetes trends .
Given a common atherosclerotic pathway, coronary artery disease (CAD) and PAD are often grouped together. There is, however, evidence that factors associated with PAD enhance susceptibility to the clinical manifestations of atherosclerosis [4,5]. Mortality among PAD patients is substantially higher than among those with CAD and even higher than many common cancers [6,7]. Despite this pessimistic prognosis, PAD has not received the same priority as CAD in research, or clinical and public health strategies, with little change in mortality rates over the past 25 years [8,9]. Thus, PAD is the cardiovascular iceberg: underdiagnosed and undertreated. Urgent action to counteract this situation is needed.
This new joint statement from the European Atherosclerosis Society (EAS) and European Society of Vascular Medicine (ESVM) is timely . The mission is two-fold; to update the evidence for two of the major modifiable cardiovascular risk factors – dyslipidaemia and thrombotic factors – and by doing so, improve awareness and management for this debilitating and deadly condition.
Dyslipidaemia and PAD
Despite previous controversy, there is now irrefutable evidence that elevated lipids are associated with increased cardiovascular risk in PAD. As for other phenotypes of atherosclerosis, apolipoprotein (apo)B-containing lipoproteins are important drivers of the clinical manifestations of this disease [11,12]. The strongest evidence comes from genetics. For example, the Million Veteran Program (MVP), a genome-wide association study, showed that variants in genes encoding the low-density lipoprotein receptor (LDLR), lipoprotein lipase (LPL), and lipoprotein(a) (LPA), in addition to variants linked with either hypercholesterolaemia or hypertriglyceridaemia, associated with PAD . Epidemiological studies are less conclusive in defining which of these apoB lipoproteins are key drivers of symptomatic PAD . Despite this, it should be emphasised that as low-density lipoprotein cholesterol (LDL-C) is causal for atherosclerotic cardiovascular disease [11,14], it should be the primary target when treating dyslipidaemia in patients with PAD.
According to the 2019 European Society of Cardiology/EAS) dyslipidaemia guidelines, PAD is categorised as very high risk (≥10% risk of a fatal cardiovascular event over 10 years). Thus, the LDL-C goal is <1.4 mmol/L (<55 mg/dL) and ≥50% reduction in LDL-C from baseline if pre-treatment values are 1.8–3.5 mmol/L (70–135 mg/dL) . Lowering LDL-C is associated with ~25% reduction in total cardiovascular events, ~30% reduction in major adverse limb events such as amputation and graft occlusion/revascularization, as well as reduction in clinical endpoints that impact walking performance and contribute to the morbidity of PAD [16,17]. In clinical practice, however, most PAD patients do not attain these goals, and management is typically inferior to that for CAD patients .
Urgent action is needed to improve the implementation of guideline-recommended LDL-C goals for PAD. This EAS/ESVM statement recommends statins as the primary lipid lowering therapy, with the combination of non-statin therapy, firstly ezetimibe, to attain LDL-C goal. A PCSK9 inhibitor may be added if LDL-C levels remain above goal (Table 1). These recommendations are supported by data from IMPROVE-IT (statin plus ezetimibe), and FOURIER and ODYSSEY OUTCOMES (statin plus a PCSK9 inhibitor) [19-21]. Given their higher absolute risk, PAD patients gain greater absolute clinical benefit from intensification of LDL-C lowering with combination therapy versus statin monotherapy, both in terms of reductions in cardiovascular events and major adverse limb events [19-21]. Indeed, FOURIER was the first randomized trial to show that the combination of a PCSK9 inhibitor and statin reduced major adverse limb events, including amputation, by 42% .
This statement also addresses the issue of statin associated muscle symptoms (often referred to as SAMS), which may be a particular clinical concern for PAD patients, impacting treatment adherence and discontinuation. The Task Force emphasises strategies to overcome SAMS, notably the use of a lower statin dose combined with a non-statin lipid-lowering therapy, to ensure that PAD patients remain on treatment and attain LDL-C goal (Table 1). With this approach, the risk of these adverse effects is outweighed by the significant clinical benefit from reduction in cardiovascular and limb adverse events.
Beyond lipids: thrombotic factors and PAD
While much of the focus of this statement is on management of dyslipidaemia, recommendations for antithrombotic therapy are also discussed. These largely derive from major prospective studies which support the benefit of dual antiplatelet therapy to prevent cardiovascular events, as well as adverse limb events following lower-extremity revascularization (Table 1). Notably, the COMPASS trial in patients with stable CAD or PAD showed that dual therapy with rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily reduced major adverse limb events including amputation by 46% . The Task Force did acknowledge a small increased bleeding risk from thrombotic therapy, as shown in both the COMPASS and the VOYAGER PAD trial in patients undergoing lower-extremity revascularization [22-24]. In their recommendations, they advocate weighing the clinical benefit from reduction in major adverse cardiovascular and limb events, including acute limb ischaemia and amputation, versus any potential bleeding risk for individual patients.
This joint statement from the EAS and the ESVM provides clinical guidance for the management of dyslipidaemia and thrombotic factors in patients with PAD. Importantly, both PCSK9 inhibitors and rivaroxaban were shown to reduce major adverse limb events, including amputation. Finally, this new guidance is another example of how collaboration between academic societies can help in achieving the United Nations Sustainable Development 2030 Agenda . Education and the use of SMART health tools are essential to translate these recommendations to clinical practice, and ultimately, improve the appalling prognosis of PAD patients.
Table 1. Key recommendations for managing peripheral arterial disease (PAD): the European Atherosclerosis Society/European Society of Vascular Medicine Task Force
|• Recommendation 1. Statins, at the highest tolerated dose, are indicated in patients with PAD for the prevention of cardiovascular events.|
• Recommendation 2. Low-density lipoprotein cholesterol (LDL-C) should be lowered to <1.4 mmol/L (<55 mg/dL) and by >50% if pre-treatment values are 1.8–3.5 mmol/L (70–135 mg/dL).
• Recommendation 3. Combination treatment with a statin and ezetimibe may be considered to improve LDL-C goal attainment. This approach could allow better tolerance of a lower dose of statin in patients with statin side effects.
• Recommendation 4. A PCSK9 inhibitor should be added if LDL-C levels remain 50% higher than goal despite statin treatment, with or without ezetimibe.
• Recommendation 5. Antiplatelet therapy is indicated to prevent further cardiovascular events. This should be either clopidogrel 75 mg/day, or the combination of aspirin 100 mg/day and rivaroxaban (2 x 2.5 mg/day).
• Recommendation 6. Dual antiplatelet therapy (DAPT) should be given for at least one month after drug coated balloon angioplasty, and for 3 months after either drug eluting or covered stent implantation.
• Recommendation 7. Based on results from the VOYAGER study, combination therapy with aspirin (100mg/day) and rivaroxaban (2 x 2.5 mg/day) should be considered for DAPT post-intervention.
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