Welcome to VascularAdviser.com, the new communication hub developed to provide information and educational resources on all areas of Vascular Protection.

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WHAT IS ‘VASCULAR PROTECTION’? 01

Vascular disease and its many manifestations, including coronary artery disease (CAD) and peripheral artery disease (PAD), have a major impact on the lives of millions of patients and those around them. Major advances in surgical and medical management strategies have helped healthcare professionals reduce its impact. However, despite these advances, the residual risk of major adverse cardiac events remains high. Research into innovative strategies to address this residual risk is ongoing. Whether it is through the use of different combinations of antithrombotic drugs, reducing lipid levels or other disease mediators, the area of Vascular Protection is exciting and continues to evolve.

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Vascular Protection: Frequently Asked Questions 02

Frequently asked questions about vascular protection

01

What is atherosclerosis?

What is atherosclerosis?

Atherosclerosis is a chronic, systemic condition that results in the build-up of lipid-rich plaques in the arteries of the body.1 Depending on the arteries affected, this may manifest as:

  • Coronary artery disease (CAD)
  • Peripheral artery disease (PAD), e.g. of the lower extremities or the carotid arteries

The formation of these plaques occurs over several decades, starting from a non-pathological lesion in the intima (the surface layer of the artery exposed to the blood) and progressing to a fibroatheroma – an advanced lesion characterized by a fibrous cap and a necrotic core.2,3 This process occurs to some extent in many individuals throughout adulthood, but it may be accelerated by a range of risk factors including diabetes, smoking or high blood cholesterol.4

Atherosclerotic lesion development
Pathological atherosclerotic lesions develop in the arterial wall over several decades.3,5,6
Model of the stages of development of atherosclerotic lesions.

The process of atherogenesis is initiated by disturbances in blood flow at so-called ‘predilection sites’, which lead to changes in the endothelial lining of the vascular system.2 These changes cause low-density lipoproteins (LDLs) to accumulate in the intima, where they become modified by oxidation and aggregation. Increasing retention of LDL triggers the recruitment of inflammatory macrophages to the intima, where they ingest the lipids to become foam cells – so-called because they are filled with cholesteryl ester droplets, giving them a foamy appearance.7 1,2,8 As the lesion progresses, these lipid-rich cells in the core of the plaque begin to die, releasing lipids and forming the necrotic core of the fibroatheroma.1 Meanwhile, smooth muscle cells migrate from the artery wall into the intima, where they proliferate to form a fibrous cap that covers the surface of the plaque.1 In some cases, over time, infiltrating macrophages and the release of active proteases can lead to thinning of this cap.3 While very large plaques may impede blood flow, causing ischaemic symptoms such as stable angina, these ‘thin-cap fibroatheromas’ are the most likely to cause an acute atherothrombotic event because they are most vulnerable to rupture, exposing the plaque contents to the blood and triggering the formation of a blood clot.1,9

References
  • Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011;473:317–325.
  • Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res 2014;114:1852–1866.
  • Yahagi K, Kolodgie FD, Otsuka F et al. Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat Rev Cardiol 2016;13:79–98.
  • Norgren L, Hiatt WR, Dormandy JA et al. Inter-society consensus for the management of peripheral artery disease (TASC II). J Vasc Surg 2007;45 Suppl S:S5–67.
  • Insull W, Jr. The pathology of atherosclerosis: plaque development and plaque responses to medical treatment. Am J Med 2009;122:S3–S14.
  • Bradberry JC. Peripheral artery disease: pathophysiology, risk factors, and role of antithrombotic therapy. J Am Pharm Assoc (2003) 2004;44:S37–44; quiz S44-35.
  • Libby P, Lichtman AH, Hansson GK. Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity 2013;38:1092–1104.
  • Tabas I, Garcia-Cardena G, Owens GK. Recent insights into the cellular biology of atherosclerosis. The Journal of cell biology 2015;209:13–22.
  • Weitz JI. Insights into the role of thrombin in the pathogenesis of recurrent ischaemia after acute coronary syndrome. Thromb Haemost 2014;112:924–931.

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02

How does atherosclerosis lead to an ischaemic event (e.g. myocardial infarction or ischaemic stroke)?

How does atherosclerosis lead to an ischaemic event (e.g. myocardial infarction or ischaemic stroke)?

Acute ischaemic events such as myocardial infarction (MI), stroke or acute limb ischaemia are caused by a sudden restriction in arterial blood flow to the heart, brain or limb. Historically, it was thought that these events were caused by narrowing of the vessel by large atherosclerotic plaques, allowing a small platelet thrombus to occlude the vessel completely.1 However, it is now understood that the majority of these events occur when a vulnerable plaque ruptures or is eroded, releasing procoagulant material into the bloodstream and leading to the formation of a large thrombus – a process known as atherothrombosis.2

Vulnerable plaques

Vulnerable plaques are atherosclerotic lesions that are at high short-term risk of thrombosis.3 The archetypal vulnerable plaque is characterized by a thin fibrous cap and an abundance of macrophage-derived foam cells beneath it.2 Eventually, the cap can no longer withstand the mechanical force of the blood pressure and the plaque may rupture.4 Alternatively, ischaemic events may be provoked by plaque erosion, a process that is poorly understood but results in the loss of the surface endothelium.3

Development of vulnerable plaques
Structure of a vulnerable plaque.
Diagram depicting the structure of a vulnerable plaque.

Formation of platelet and fibrin-rich arterial thrombi

When a vulnerable plaque ruptures, the contents of the plaque become exposed to the blood with important clinical consequences:5

  • Exposure of tissue factor in the lipid core leads to thrombin generation and activation of the coagulation cascade, culminating in the formation of fibrin which stabilizes the clot and facilitates its growth
  • At the same time, collagen and von Willebrand factor in the subendothelial layer adhere to platelets, resulting in the rapid recruitment of additional platelets to the site to form a platelet plug. Thrombin further contributes to activating platelets

The activation of these two pathways concurrently allows for the rapid generation of a large thrombus, rich in both fibrin and platelets.6 If sufficiently large, this thrombus may substantially or even completely occlude the artery, restricting blood flow and causing an acute ischaemic event.

References
  • Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013;368:2004–2013.
  • Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011;473:317–325.
  • Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res 2014;114:1852–1866.
  • Hansson GK, Libby P, Tabas I. Inflammation and plaque vulnerability. J Intern Med 2015;278:483-493.
  • Weitz JI. Insights into the role of thrombin in the pathogenesis of recurrent ischaemia after acute coronary syndrome. Thromb Haemost 2014;112:924–931.
  • Yamashita A, Sumi T, Goto S et al. Detection of von Willebrand factor and tissue factor in platelets-fibrin rich coronary thrombi in acute myocardial infarction. Am J Cardiol 2006;97:26–28.

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03

What are the factors that increase the risk of atherothrombotic disease?

What are the factors that increase the risk of atherothrombotic disease?

Numerous factors are associated with an increased risk of atherothrombotic disease. Traditional risk factors include:1

  • Elevated cholesterol
  • Hypertension
  • Smoking
  • Diabetes
  • Male gender
  • Increasing age

These traditional risk factors are included in all guideline-recommended risk calculators used to estimate cardiovascular (CV) risk in patients without documented CV disease (such as the SCORE system recommended by the European Society of Cardiology [ESC], the pooled cohort studies equation recommended by the American College of Cardiology/American Heart Association [ACC/AHA] and QRISK1/2 recommended by the UK National Institute for Health and Care Excellence [NICE]).2

More recently, several additional factors have been associated with an increased risk of CV disease. These include:2,3

  • A family history of early onset CV disease
  • Moderate or severe chronic kidney disease
  • Psychosocial risk factors (such as low socioeconomic status, depression and stress)
  • Inflammatory and autoimmune disease (such as rheumatoid arthritis and systemic lupus erythematosus)
  • Erectile dysfunction in men

Many of these factors are included in the most recent version of the QRISK estimator – QRISK 3.3

Although atherosclerosis is a systemic disease with overlapping risk factors, the relative importance of different risk factors appears to be subtly different in patients with different manifestations of the disease. One study showed that the leading risk factors for myocardial infarction (MI) were dyslipidemia, current smoking and psychosocial factors,4 whereas for peripheral artery disease (PAD), smoking, diabetes and hypertension appear most important.5 Modifying these risk factors, both through lifestyle modifications and medication targeted at controlling cholesterol, blood pressure and diabetes, is a cornerstone of prevention in patients with atherosclerotic disease.2,6,7

References
  • Mozaffarian D, Wilson PW, Kannel WB. Beyond established and novel risk factors: lifestyle risk factors for cardiovascular disease. Circulation 2008;117:3031–3038.
  • Piepoli MF, Hoes AW, Agewall S et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The sixth joint task force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315–2381.
  • Hippisley-Cox J, Coupland C, Brindle P. Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study. Bmj 2017;357:j2099.
  • Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937–952.
  • Fowkes FG, Rudan D, Rudan I et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382:1329–1340.
  • Tendera M, Aboyans V, Bartelink ML et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2851–2906.
  • Montalescot G, Sechtem U, Achenbach S et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the Management of Stable Coronary Artery Disease of the European Society of Cardiology. Eur Heart J 2013;34:2949–3003.

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04

Why are patients with known disease in one arterial bed at risk of atherothrombotic events in another?

Why are patients with known disease in one arterial bed at risk of atherothrombotic events in another?

Coronary artery disease (CAD), peripheral artery disease (PAD) and cerebrovascular/carotid artery disease share a common underlying pathophysiology, atherosclerosis,1,2 as well as overlapping risk factors (including dyslipidemia, hypertension, diabetes mellitus and smoking).3 Atherosclerotic plaques may therefore develop in multiple arterial beds at the same time, which means a diagnosis of disease in one bed may be a symptom of widespread atherosclerosis4 – in fact, patients with PAD are more likely to experience an ischaemic event in the heart or brain in the first five years after presentation than in the peripheral arteries.5 The likelihood of patients experiencing atherosclerotic disease in multiple arterial beds is highlighted by data from the prospective REACH registry, which enrolled approximately 68,000 patients with symptomatic cardiovascular (CV) disease or risk factors for atherothrombotic events.6 In this population, approximately 25% of patients with CAD and 62% of patients with PAD had documented disease in at least one additional bed.4 This is clinically significant because polyvascular disease (symptomatic disease affecting two or more arterial beds) is associated with a particularly high risk of major CV events, and the prognosis worsens as the number of affected arterial beds increases.4,7,8 In REACH, the risk of major adverse CV events in patients with polyvascular disease was almost double that observed in those with disease in a single arterial bed at 1 year and 3 years follow-up.4,7 Similar findings were also reported in the CRUSADE registry, where all-cause mortality rates at 3 years increased from 33% in patients with CAD alone, to 59% in patients with disease in all three arterial beds.8

Polyvascular disease in the REACH registry
Patients with polyvascular disease in the REACH registry.4
A large proportion of patients in the REACH registry had polyvascular disease.

While the degree of overlap between CAD, PAD and cerebrovascular disease reported in registries such as REACH is striking, it is likely to underestimate the true incidence of polyvascular disease because these diseases are frequently undiagnosed. In the IPSILON study, general practitioners used the ankle–brachial index (ABI) to assess peripheral stenosis in 1340 patients with CAD and no known PAD.9 PAD was identified in 27% of these patients; 16% had no symptoms of PAD. Taken together with registry data on known polyvascular disease, these data demonstrate that a patient with documented arterial disease in one bed is at risk of an ischaemic event in any arterial bed – even if no additional symptoms are present.

References
  • Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013;368:2004–2013.
  • Hiatt WR, Armstrong EJ, Larson CJ, Brass EP. Pathogenesis of the limb manifestations and exercise limitations in peripheral artery disease. Circ Res 2015;116:1527–1539.
  • Bhatt DL, Steg PG, Ohman EM et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295:180–189.
  • Steg PG, Bhatt DL, Wilson PW et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297:1197–1206.
  • Hirsch AT, Haskal ZJ, Hertzer NR et al. ACC/AHA 2005 Practice guidelines for the management of patients with peripheral artery disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Artery Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006;113:e463–e654.
  • Ohman EM, Bhatt DL, Steg PG et al. The REduction of Atherothrombosis for Continued Health (REACH) Registry: an international, prospective, observational investigation in subjects at risk for atherothrombotic events-study design. Am Heart J 2006;151:786e781–710.
  • Alberts MJ, Bhatt DL, Mas JL et al. Three-year follow-up and event rates in the international REduction of Atherothrombosis for Continued Health Registry. Eur Heart J 2009;30:2318–2326.
  • Subherwal S, Bhatt DL, Li S et al. Polyvascular disease and long-term cardiovascular outcomes in older patients with non-ST-segment-elevation myocardial infarction. Circ Cardiovasc Qual Outcomes 2012;5:541–549.
  • Kownator S, Cambou JP, Cacoub P et al. Prevalence of unknown peripheral artery disease in patients with coronary artery disease: data in primary care from the IPSILON study. Arch Cardiovasc Dis 2009;102:625–631.

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05

How are patients with coronary artery disease currently managed?

How are patients with coronary artery disease currently managed?

The overarching aims of the treatment of coronary artery disease (CAD) are to reduce symptoms and improve prognosis. The management of CAD includes patient education and interventions to:1,2

  • Control symptoms
  • Limit further progression of atherosclerosis through control of cardiovascular (CV) risk factors
  • Prevent potentially fatal ischaemic events and improve survival

Management of angina symptoms

Control of CAD symptoms involves the use of anti-ischaemic drugs to provide angina relief:1,2

  • First-line therapies consist of short-acting nitrates to cause coronary vasodilatation with beta-blockers and/or calcium channel blockers to control heart rate, increase perfusion to ischaemic areas and promote vasodilation
  • Second-line therapies include long-acting nitrates and ranolazine – an inhibitor of the late sodium current

If symptoms persist despite optimal medical therapy, revascularization may be indicated to provide symptom relief in patients with any coronary stenosis >50%.1,3 Revascularization may also be indicated to improve prognosis in patients with severe stenosis in multiple arteries or in one very significant artery (e.g. the left main coronary artery).3

Cardiovascular risk factor control

CV risk factor control is best achieved as part of coordinated, multidisciplinary programme that should include:1,2,4

  • Patient education
  • Smoking cessation advice and support
  • Lifestyle changes promoting lipid, blood pressure and diabetes control (e.g. regular physical exercise, adopting a healthy diet, following a weight-management programme)
  • Use of medical therapies aiding lipid, blood pressure and diabetes control (e.g. statins, antihypertensives, insulin/glycaemic control medication)
  • Psychosocial management, such as social support and treatment of underlying conditions such as depression and anxiety

Protection against CV events

For protection against major CV events, all patients with CAD should receive:1,2

  • Single antiplatelet therapy with acetylsalicylic acid (ASA), or clopidogrel as an alternative in case of ASA intolerance
  • A statin to reduce blood low-density lipoprotein (LDL) levels

Guidelines also recommend additional therapies for protection against CV events in patients with certain co-morbidities:1,2

  • An angiotensin-converting enzyme (ACE) inhibitor (or an angiotensin receptor blocker [ARB] as an alternative) in patients with hypertension, heart failure (with a left ventricular ejection fraction [LVEF] ≤40%), diabetes or chronic kidney disease
  • Beta-blockers in patients with CAD who have experienced an acute coronary syndrome (ACS) within the previous 3 years or who have heart failure (with a LVEF ≤40%)

Recently, a number of new medications have also been shown to reduce CV events in patients with atherosclerotic disease and co-morbidities,4 including liraglutide and empagliflozin for glucose control in type 2 diabetes, and evolocumab and alirocumab for lipid control (see here for more information). Ongoing trials are also evaluating optimal treatments for secondary prevention of CV events in patients with atherosclerotic disease, and these results are likely to hold great promise for physicians and patients alike.

References
  • Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2012;126:e354–471.
  • Montalescot G, Sechtem U, Achenbach S et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the Management of Stable Coronary Artery Disease of the European Society of Cardiology. Eur Heart J 2013;34:2949–3003.
  • Windecker S, Kolh P, Alfonso F et al. 2014 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2014;35:2541–2619.
  • Cortés-Beringola A, Fitzsimons D, Pelliccia A et al. Planning secondary prevention: Room for improvement. Eur J Prev Cardiol 2017;24:22–28.

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06

How are patients with peripheral artery disease currently managed?

How are patients with peripheral artery disease currently managed?

The overarching aims of the treatment of peripheral artery disease (PAD) are to reduce symptoms and to improve prognosis.1,2 The management of PAD includes lifestyle modifications, medical therapies and, in some instances, revascularization to:

  • Improve limb symptoms
  • Limit further progression of atherosclerosis through the control of cardiovascular (CV) risk factors
  • Prevent potentially fatal ischaemic events
  • Minimize tissue loss/need for amputation

Because of the systemic nature of the underlying disease, a multidisciplinary approach is warranted to establish an effective management strategy.1-3

Management of limb symptoms

Patients with PAD typically present with leg pain (e.g. intermittent claudication) and this can limit their daily activities and impact on their quality of life.3 Management of limb symptoms involves:

  • A supervised and structured exercise programme
  • Medical therapies aimed at reducing limb symptoms by suppressing platelet aggregation and promoting vasodilation1,3

If no improvements in limb symptoms are seen after 3–6 months of conservative therapy (CV risk factor control, structured exercise programme and medical therapy for limb symptoms), revascularization may be considered.1,2

CV risk factor control

The control of CV risk factors is essential to limit further progression of the underlying atherosclerosis causal to PAD. Key interventions include:1-3

  • Smoking cessation advice and support
  • Lifestyle changes promoting lipid, blood pressure and diabetes control (e.g. regular physical exercise, adopting a healthy diet, and following a weight-management programme)
  • Use of medical therapies aiding lipid, blood pressure and diabetes control (e.g. statins, antihypertensives and insulin/glycaemic-control medication)

Protection against cardiovascular events

Prevention of major CV events is achieved by pharmacological or lifestyle interventions that reduce plaque progression, stabilize plaques (by reducing inflammation) and prevent thrombosis, should plaque rupture or erosion occur.4

For protection against major CV events, all patients with symptomatic PAD should receive:1-3

  • Single antiplatelet therapy with acetylsalicylic acid (ASA), or clopidogrel as an alternative in case of ASA intolerance
  • A statin to reduce blood low-density lipoprotein (LDL) levels

In patients with PAD and hypertension, antihypertensive agents are also recommended to reduce blood pressure.1

Tissue loss minimization/
amputation avoidance

Between 10–21% of patients with intermittent claudication may experience worsening of disease and develop critical limb ischaemia,5,6 which is associated with chronic ischaemic rest pain, non-healing wounds/ulcers and gangrene.1 In these patients, as well as in patients with acute limb ischaemia and a salvageable limb, revascularization is indicated to minimize tissue loss/avoid amputation. Amputation may become necessary in some patients with irreversible tissue damage.1,2

References
  • Gerhard-Herman MD, Gornik HL, Barrett C et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;69:e71–e126.
  • Tendera M, Aboyans V, Bartelink ML et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2851–2906.
  • Conte MS, Pomposelli FB, Clair DG et al. Society for Vascular Surgery practice guidelines for atherosclerotic occlusive disease of the lower extremities: management of asymptomatic disease and claudication. J Vasc Surg 2015;61:2s–41s.
  • Montalescot G, Sechtem U, Achenbach S et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the Management of Stable Coronary Artery Disease of the European Society of Cardiology. Eur Heart J 2013;34:2949–3003.
  • Sigvant B, Lundin F, Wahlberg E. The risk of disease progression in peripheral artery disease is higher than expected: a meta-analysis of mortality and disease progression in peripheral artery disease. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery 2016;51:395–403.
  • Norgren L, Hiatt WR, Dormandy JA et al. Inter-society consensus for the management of peripheral artery disease (TASC II). J Vasc Surg 2007;45 Suppl S:S5–67.

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07

What is meant by the concept of vascular protection?

What is meant by the concept of vascular protection?

Vascular protection is a comprehensive strategy aimed at preventing potentially fatal ischaemic events, such as myocardial infarction (MI) and stroke, in patients with cardiovascular (CV) disease due to atherosclerosis. Ischaemic events are typically precipitated by atherothrombosis, the formation of platelet- and fibrin-rich arterial thrombi on the vascular wall at the site of atherosclerotic plaque rupture (or erosion).1,2

There are several key elements of vascular protection:3,4

  • CV risk factor control through lifestyle changes
  • Medical therapies to limit atherosclerosis progression and stabilize existing plaques, making them less prone to rupture/erosion
  • Antithrombotic therapies (e.g. with single antiplatelet therapy in patients with stable CV disease) to prevent blood clot formation over any ruptured/eroded atherosclerotic plaques

These elements are summarized in the figure below:

Vascular protection strategies
Current strategies for vascular protection in patients with CAD.3,4
Vascular protection involves cardiovascular risk factor control and use of antithrombotic therapies to prevent blood clot formation.

Patients who have had an ischaemic event remain at increased CV risk indefinitely, so it is essential that all elements of a vascular protection strategy are evaluated to ensure that patients are optimally managed. Adjustment of secondary prevention strategies might include intensifying antithrombotic therapy for patients judged at high risk, or using newer medications to improve management of blood pressure, lipid-lowering or glucose control.4

References
  • Yamashita A, Sumi T, Goto S et al. Detection of von Willebrand factor and tissue factor in platelets-fibrin rich coronary thrombi in acute myocardial infarction. Am J Cardiol 2006;97:26–28.
  • Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013;368:2004–2013.
  • Montalescot G, Sechtem U, Achenbach S et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the Management of Stable Coronary Artery Disease of the European Society of Cardiology. Eur Heart J 2013;34:2949–3003.
  • Cortés-Beringola A, Fitzsimons D, Pelliccia A et al. Planning secondary prevention: Room for improvement. Eur J Prev Cardiol 2017;24:22–28.

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08

What does vascular protection mean for patients with coronary artery disease?

What does vascular protection mean for patients with coronary artery disease?

Patients with coronary artery disease (CAD) are at high risk of potentially fatal ischaemic events, such as myocardial infarction (MI) and stroke. While this risk is highest in the first 6–12 months after an acute coronary event,1 during which guidelines recommend more aggressive antithrombotic therapies,2,3 patients remain at risk long after the first year.4 In the recent PEGASUS-TIMI 54 trial, which enrolled patients 1–3 years after an MI, 9% of patients on standard therapy experienced a major cardiovascular (CV) event over the 3-year follow-up period.5 Even patients who received a more aggressive antiplatelet strategy (ticagrelor 60 mg bid plus acetylsalicylic acid [ASA]) had an 8% residual risk of major adverse CV events, highlighting the high risk in this population despite optimized antiplatelet therapy.

These data are supported by real-world data from the multinational REACH registry, which included 40,258 patients with documented CAD. Despite the majority of patients receiving guideline-recommended secondary prevention strategies,6 approximately 5% and 12% of patients with CAD experienced a major CV event at 1 year and 3 years follow-up, respectively.7

Together, these data from clinical trials and routine clinical practice demonstrate the high residual risk of major CV events in patients with CAD, despite guideline-recommended therapies. To address this, it is essential that patients receive a comprehensive long-term vascular protection strategy to manage all aspects of their condition. Several recent clinical trials have led to the approval of agents for improved long-term thrombosis prevention,5,8 lipid control9 and blood glucose management,10,11 and further trials in these areas are ongoing.

References
  • Fox KAA, Carruthers KF, Dunbar DR et al. Underestimated and under-recognized: the late consequences of acute coronary syndrome (GRACE UK-Belgian Study). Eur Heart J 2010;31:2755–2764.
  • Roffi M, Patrono C, Collet JP et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267–315.
  • Steg PG, James SK, Atar D et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology (ESC). Eur Heart J 2012;33:2569–2619.
  • Abu-Assi E, López-López A, González-Salvado V et al. The Risk of Cardiovascular Events After an Acute Coronary Event Remains High, Especially During the First Year, Despite Revascularization. Rev Esp Cardiol (Engl Ed) 2016;69:11–18.
  • Bonaca MP, Bhatt DL, Cohen M et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791–1800.
  • Bhatt DL, Steg PG, Ohman EM et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295:180–189.
  • Alberts MJ, Bhatt DL, Mas JL et al. Three-year follow-up and event rates in the international REduction of Atherothrombosis for Continued Health Registry. Eur Heart J 2009;30:2318–2326.
  • Morrow DA, Braunwald E, Bonaca MP et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012;366:1404–1413.
  • Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–1722.
  • Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–2128.
  • Marso SP, Daniels GH, Brown-Frandsen K et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–322.

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09

What does vascular protection mean for patients with peripheral artery disease?

What does vascular protection mean for patients with peripheral artery disease?

While the treatment of coronary artery disease (CAD) has progressed dramatically over the past 50 years, peripheral artery disease (PAD) treatment has faced several issues:

  • Under-diagnosis of PAD
  • A lack of effective treatments for in PAD
  • A failure to treat diagnosed patients in line with current best practice

Estimates indicate that over half of patients with PAD are asymptomatic,1 while 10–35% present with intermittent claudication2 – a feeling of tightness or ‘pins and needles’ in the leg which is often disregarded by the patient. These factors mean that patients frequently remain undiagnosed until the disease is very advanced – over half of patients undergoing major amputation for critical limb ischaemia may have had no ischaemic symptoms at all as little as six months earlier.3

Even after diagnosis of PAD, treatment options remain limited. Current guidelines recommend that patients with PAD are treated with an antiplatelet agent (either acetylsalicylic acid [ASA] or clopidogrel) in combination with a statin and, where indicated, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to manage blood pressure4. The recommendation to consider antithrombotic therapy with clopidogrel is based on a subanalysis of the CAPRIE trial in 19965; while several more recent clinical trials have included a PAD population,6-9 the PEGASUS trial for ticagrelor in patients with a history of myocardial infarction (MI) showed an improvement in the risk of major adverse cardiovascular (CV) events in the PAD subgroup.10 All of these trials indicate a high residual risk of major CV events, with ~1 in 10 patients experiencing a major CV event over the 2.5–3-year follow-up period.6,8-10

While patients in clinical trials usually receive guideline-recommended therapies for vascular protection, real-world data suggest that these strategies are underutilized in patients with PAD. In REACH, ~1 in 5 patients with PAD did not receive an antiplatelet agent, and almost 1 in 3 did not receive a statin. Other data indicate an even lower use of guideline-recommended therapies – in a survey of US patients with PAD attending outpatient clinics between 2006 and 2013, just over one-third of patients received an antiplatelet or a statin.11

Together, these data demonstrate an urgent need to improve vascular protection strategies in patients with PAD. Over 80% of patients with PAD are current or former smokers and 12–20% have diabetes12, making smoking cessation and diabetes control crucial in managing the disease. Meanwhile, clinical trials continue to investigate new therapeutic strategies in this population, and as more data becomes available there is hope that these may significantly reduce CV risk in these patients.

References
  • Belch JJ, Topol EJ, Agnelli G et al. Critical issues in peripheral artery disease detection and management: a call to action. Arch Intern Med 2003;163:884–892.
  • Norgren L, Hiatt WR, Dormandy JA et al. Inter-society consensus for the management of peripheral artery disease (TASC II). J Vasc Surg 2007;45 Suppl S:S5-67.
  • Peach G, Griffin M, Jones KG et al. Diagnosis and management of peripheral artery disease. BMJ 2012;345:e5208.
  • Gerhard-Herman MD, Gornik HL, Barrett C et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;69:e71–e126.
  • CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339.
  • Cacoub PP, Bhatt DL, Steg PG et al. Patients with peripheral artery disease in the CHARISMA trial. Eur Heart J 2009;30:192–201.
  • Patel MR, Becker RC, Wojdyla DM et al. Cardiovascular events in acute coronary syndrome patients with peripheral artery disease treated with ticagrelor compared with clopidogrel: Data from the PLATO Trial. Eur J Prev Cardiol 2015;22:734–742.
  • Hiatt WR, Fowkes FG, Heizer G et al. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N Engl J Med 2017;376:32–40.
  • Bonaca MP, Scirica BM, Creager MA et al. Vorapaxar in patients with peripheral artery disease: results from TRA2{degrees}P-TIMI 50. Circulation 2013;127:1522–1526.
  • Bonaca MP, Bhatt DL, Storey RF et al. Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease. J Am Coll Cardiol 2016;67:2719–2728.
  • Berger JS, Ladapo JA. Underuse of prevention and lifestyle counseling in patients with peripheral artery disease. J Am Coll Cardiol 2017;69:2293–2300.
  • Hirsch AT, Haskal ZJ, Hertzer NR et al. ACC/AHA 2005 Practice guidelines for the management of patients with peripheral artery disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Artery Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006;113:e463–e654.

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