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CAD is a dynamic process, and lifestyle modifications, medication or surgical interventions can cause disease stabilization or regression. The disease is chronic and can have long clinically silent periods, but can also become unstable at any time, usually due to an acute event. To emphasize this, the 2019 European Society of Cardiology (ESC) guidelines introduced the term “chronic coronary syndromes” (CCS) to replace the older term “stable CAD”, which gave the impression that patients were at low risk of ischaemic events.1 Read the newsletter ‘From stable CAD to chronic coronary syndromes: Evolving terminology in cardiovascular disease’ to find out more about these changes in terminology.
For protection against major cardiovascular events in patients with CCS, the 2019 ESC guidelines recommend:1
For long-term secondary prevention in patients with CCS, the 2019 ESC guidelines recommend:1
The 2019 ESC guideline recommendations for secondary prevention in patients with chronic coronary syndromes
The 2019 ESC guidelines recommend considering adding a second antithrombotic drug to antiplatelet therapy in patients with moderate or high ischaemic risk
The 2019 ESC guidelines on diabetes, pre-diabetes and cardiovascular diseases also specify that adding a second antithrombotic drug should be considered in patients with CCS and diabetes.2
Both 2019 ESC guidelines specify that adding a second antithrombotic drug should only be considered in patients without high bleeding risk.1,2 The recommended options for the second antithrombotic drug include:1
Control of CAD symptoms involves the use of anti-ischaemic drugs to provide angina relief:1,3
If symptoms persist despite optimal medical therapy, revascularization may be indicated to provide symptom relief in patients with major coronary stenosis.3,4
Professor Stuart Connolly discusses progress in CAD treatment.
How CAD treatment has changed
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Management of patients with PAD involves the prevention of major thrombotic events and the control of symptoms. To prevent the thrombotic events, practice guidelines recommend a combination of risk factor management (lipid and blood pressure control) and antithrombotic therapy.2,5-8
Traditionally, antithrombotic therapy has taken the form of single antiplatelet therapy, recommended in both the 2016 American Heart Association/American College of Cardiology (AHA/ACC) guidelines and the 2017 European Society of Cardiology (ESC) guidelines.5,6 However, data from the recent COMPASS trial6,7 have led to the evolution of these guidelines. The 2019 Global Vascular Guidelines and the 2019 European Society for Vascular Medicine (ESVM) guidelines both suggest considering dual pathway inhibition for patients with symptomatic PAD and without a high risk of bleeding.7,8 For more details about DPI therapy, please see the What is dual pathway inhibition? section. Furthermore, the 2019 ESC guidelines on diabetes, pre-diabetes and cardiovascular diseases recommend considering dual pathway inhibition for diabetes patients with concomitant symptomatic PAD, and the 2019 ESC guidelines on chronic coronary syndromes suggest considering a second antithrombotic agent (such as the COMPASS regimen) in patients at high ischaemic risk, such as those with concomitant PAD.1,2
In addition to their thrombotic risk, patients with PAD often present with leg pain (e.g. intermittent claudication), and this can limit their daily activities and impact on their quality of life.9 The 2016 AHA/ACC guidelines, 2017 ESC guidelines and 2019 ESVM guidelines recommend a supervised and structured exercise programme together with medical therapies aimed at reducing limb symptoms by suppressing platelet aggregation and promoting vasodilation to manage the limb symptoms in patients with PAD.5-7 If no improvements in limb symptoms are seen after conservative therapy, revascularization may be considered.5-7
Professor John Eikelboom discusses progress in PAD treatment.
How PAD treatment has changed
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Lower extremity revascularization may relieve the symptoms of patients with PAD,7,12 but at a risk of post-operative complications such as surgical site infection and bleeding.13 Therefore, it is necessary to carefully evaluate if the benefits from revascularization outweigh the risks of the procedure.
Current practice guidelines provide an overview of patients who may benefit from revascularization. Based on the 2017 European Society of Cardiology (ESC) guidelines and the 2019 European Society of Vascular Medicine (ESVM) guidelines, revascularization should be considered for patients with intermittent claudication only when their daily lives are compromised despite exercise therapy.6,7 However, for patients with critical limb threatening ischaemia, the 2017 ESC guidelines, 2019 ESVM guidelines and 2019 Global Vascular Guidelines indicate revascularization whenever feasible to salvage the limb.6-8
Following a peripheral revascularization procedure, patients are at a high risk of thrombotic events.14,15 Therefore, optimal antithrombotic therapy in these patients is essential.
Recent guidelines, however, vary in their recommended antithrombotic treatment after peripheral revascularization. The medication options after surgical revascularization include single antiplatelet therapy (2017 European Society of Cardiology [ESC] guidelines and 2019 European Society for Vascular Medicine [ESVM] guidelines), vitamin K antagonists (2017 ESC guidelines and 2019 ESVM guidelines) and dual antiplatelet therapy (DAPT) for specific cases of below the knee prosthetic bypass grafting (2017 ESC guidelines and 2019 ESVM guidelines) or prosthetic bypass surgery (2019 Global Vascular Guidelines).6,8
After endovascular revascularization, the guidelines suggest antiplatelet therapy. The 2017 ESC guidelines and 2019 ESVM guidelines suggest long-term single antiplatelet therapy after peripheral endovascular revascularization.6,7 The 2017 ESC guidelines, 2019 ESVM guidelines and 2019 Global Vascular Guidelines recommend considering DAPT in patients after endovascular revascularization.6,7,16 The 2016 American Heart Association/American College of Cardiology (AHA/ACC) guideline on the management of patients with lower extremity peripheral artery disease (PAD) also suggest DAPT in patients with symptomatic PAD after revascularization.5 However, the recommendations on DAPT for the prevention of thrombotic events after peripheral endovascular revascularization are based on clinical judgement and consensus because the data from clinical trials is limited.5-8 This shows that there is a lack of data based evidence for the efficiency of DAPT for preventing thrombotic events in patients with symptomatic PAD.
More recently, the VOYAGER PAD clinical trial demonstrated that dual pathway inhibition can significantly reduce major adverse limb events in patients with symptomatic PAD following revascularization without a significant increase in major bleeding, offering a new therapeutic approach in this clinical setting.17
For more information, please see How can outcomes be improved in patients with symptomatic peripheral artery disease (PAD)?
Two pathways contribute to arterial thrombosis: platelet activation and the activation of the coagulation cascade.18 Dual pathway inhibition is an antithrombotic regimen composed of a low-dose anticoagulant and an antiplatelet. This combination targets both pathways to reduce the risk of cardiovascular events.18,19
Dual pathway inhibition targets platelet activation and the activation of coagulation cascade
The mechanism of action of dual pathway inhibition
The evidence for the benefit of dual pathway inhibition comes from the COMPASS study, which enrolled 27,395 patients with stable atherosclerotic disease who were already receiving a high standard of treatment.9
The COMPASS regimen was associated with a significant 24% reduction in the composite risk of myocardial infarction, stroke and cardiovascular death compared with an antiplatelet alone.9
As would be expected given the use of an additional antithrombotic, the COMPASS regimen was associated with a significant increase in major bleeding compared with an antiplatelet alone, although there were no significant differences in the risks of intracranial haemorrhage or fatal bleeding.9
The benefit of the COMPASS regimen was found to be especially high in patients with coronary artery disease and/or peripheral artery disease and high vascular risk, including patients with polyvascular disease, heart failure, renal insufficiency (estimated glomerular filtration rate 15–60 ml/min) or diabetes.20 More information can be found in the risk stratification newsletter.
Additional support for the efficacy and safety of dual pathway inhibition comes from the VOYAGER PAD study, which enrolled patients with symptomatic peripheral artery disease undergoing revascularization procedures. In this patient population, dual pathway inhibition significantly reduced limb ischaemia and major cardiovascular events in comparison to antiplatelet therapy. Additionally, TIMI major bleeding did not significantly increase with dual pathway inhibition compared with antiplatelet therapy.17
The COMPASS trial explained.
Video explaining the results of the COMPASS trial
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The VOYAGER PAD trial explained.
Video explaining the results of the VOYAGER PAD trial
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Cardiovascular (CV) risk factor control is best achieved as part of coordinated, multidisciplinary programme that should include:1,3,21
The COMPASS study has shown that, in patients with CAD, vascular protection with dual pathway inhibition can provide additional protection against myocardial infarction, stroke and CV death compared with an antiplatelet alone.9 Although addition of a second antithrombotic was associated with an increased risk of major bleeding, there were no significant increases in the risks of intracranial haemorrhage and fatal bleeding.9
The COMPASS regimen is indicated for the prevention of atherothrombotic events in adult patients with CAD or peripheral artery disease at high risk of ischaemic events.22
The 2019 ESC guidelines recommend that the COMPASS regimen should be considered for the treatment of patients with chronic coronary syndromes at high risk of ischaemic events and without high risk of bleeding.1
The COMPASS trial explained.
Video explaining the results of the COMPASS trial
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The overarching aims of the treatment of symptomatic PAD are to reduce symptoms and to improve prognosis.5,6 The management of symptomatic PAD includes lifestyle modifications, medical therapies and, in some instances, revascularization to:
A multidisciplinary approach is warranted to establish an effective management strategy for patients with symptomatic PAD.6,11
Antithrombotic therapy is crucial for the protection against thrombotic events in patients with symptomatic PAD, but clinical trials investigating intensified antiplatelet regimens have been largely unsuccessful in patients with symptomatic PAD.23-25
Recently, two large randomized controlled trials have demonstrated the benefits of dual pathway inhibition in patients with PAD. The COMPASS trial included patients with mostly chronic PAD, and the VOYAGER PAD trial included patients with symptomatic PAD undergoing peripheral revascularization procedures.10,17
Patients with PAD in the COMPASS study were found to benefit from vascular protection with dual pathway inhibition compared with an antiplatelet alone.9,10 Not only did this regimen reduce the risk of myocardial infarction, stroke and CV death by 28% versus an antiplatelet alone, it also reduced the risk of major adverse limb events by 46%.9,10 Although the addition of an additional antithrombotic was associated with an increased risk of major bleeding, there were no significant increases in the risks of intracranial haemorrhage or fatal bleeding.9,10 The success of this study led to indication of the COMPASS regimen for the prevention of atherothrombotic events in adult patients with symptomatic PAD at high risk of ischaemic events.22
The benefit of dual pathway inhibition for patients with PAD that were first seen in the COMPASS trial was also investigated in the VOYAGER PAD trial which assessed the efficacy and safety of dual pathway inhibition versus single antiplatelet therapy in patients with symptomatic PAD undergoing lower extremity revascularization.17 The results of the study showed that dual pathway inhibition reduced the risk of composite outcome (acute limb ischaemia, major amputation of vascular aetiology, myocardial infarction, ischaemic stroke or cardiovascular death) by 15% compared with antiplatelet therapy.17 Additionally, TIMI major bleeding did not significantly increase with dual pathway inhibition compared with antiplatelet therapy.17
The COMPASS regimen is indicated for the prevention of atherothrombotic events in adult patients with coronary artery disease and symptomatic peripheral artery disease at high risk of ischaemic events.22
In the COMPASS trial, a high baseline risk of events means that patients with heart failure, diabetes and renal impairment (estimated glomerular filtration rate 15–60 ml/min) were among those who derived the largest benefit from vascular protection with dual pathway inhibition compared with an antiplatelet alone.20 (Please see the Which patients can benefit most from vascular protection? section)