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Chapter 4
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Current andEmerging Therapies
forAtherosclerosis
AdamJ.Nelson andStephenJ.Nicholls
Key Learning Points
Lifestyle intervention, although difcult to sustain, remains the foundation of
•
atherosclerosis treatment. Cardiac rehabilitation may be an underappreciated
catalyst.
• A number of emerging agents are in varying stages of development and are tar-
geting the full spectrum of atherosclerotic biology from lipids through to inam-
mation and thrombosis.
• Studies of emerging agents have re-emphasized the presence of a number of high
risk groups including those with peripheral arterial disease and those who have
sustained recent events.
• Risk assessment is likely to aid in determining how to use emerging agents: high-
est risk patients are likely to derive greatest overall benet. Current risk assess-
ment tools, however, are limited and may not represent key subgroups
4.1 Introduction
Atherosclerotic cardiovascular disease (ASCVD) continues to be a major global
public health challenge. Despite therapeutic advances and their associated reduction in morbid and mortal cardiovascular events, ASCVD remains a leading cause
of death and drain on health care expenditure worldwide. Many patients continue
to experience clinical events, despite the use of evidenced-based therapies, supporting the need to identify additional strategies to achieve greater reductions in
A. J. Nelson
Duke Clinical Research Institute, Monash University, Melbourne, Australia
S. J. Nicholls (
Monash Cardiovascular Research Centre, Monash University, Melbourne, Australia
e-mail: stephen.nicholls@monash.edu
R. Fitridge (ed.), Mechanisms of Vascular Disease,
https://doi.org/10.1007/978-3-030-43683-4_4
*)
71© Springer Nature Switzerland AG 2020
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cardiovascular risk. Given the systemic nature of atherosclerosis, increasing evidence has demonstrated that the clinical benets primarily targeted to reduce coronary events extend to other vascular territories. This has major implications for the
development of guidelines for prevention of coronary, cerebrovascular and peripheral vascular disease.
A. J. Nelson and S. J. Nicholls
4.2 Risk Stratication
Optimal approaches to cardiovascular prevention will require careful denition of
the risk that an individual has of experiencing a clinical event. With an ageing population, lifelong risk of cardiovascular disease will ultimately increase. However,
making decisions to intensify risk reduction strategies can be challenging. Early
commencement of multiple medical therapies to reduce the risk of a clinical event
many decades in the future is unlikely to be cost effective and unnecessarily exposes
a large number of individuals to medications associated with side effects.
Considerable work has been undertaken to more effectively determine the absolute
risk that an individual has of experiencing a cardiovascular event, with those at the
highest level of risk receiving more intensive therapy, as they are likely to derive the
greatest absolute benet from their use.
The patient with clinically manifest atherosclerotic disease, regardless of vascular territory involved, has the greatest absolute risk of a subsequent cardiovascular
event. These are the patients typically enrolled in most clinical trials and receive the
greatest clinical benet from established therapies. Accordingly, the presence of
symptomatic atherosclerotic cardiovascular disease identies a patient who should
receive intensive risk factor modication in prevention guidelines.
An increase in the number of evidence-based therapies is likely to have important consequences for both the health economy (payers) and for patients; greater pill
burden, medication interactions and adverse drug reactions, inconvenience and
potential out of pocket cost. These factors are likely to inuence how these agents
are best applied to derive net clinical benet in the context of aggressive risk
modication.
The association of concomitant risk factors, recurrent clinical events and presence of polyvascular disease (atherosclerotic disease in multiple arterial beds) are
increasingly being integrated into clinical risk algorithms to determine how to more
optimally risk stratify patients in secondary prevention [
Primary prevention of atherosclerotic cardiovascular disease presents a more
challenging scenario. While lifelong risk of cardiovascular events across the population is considerable, the ability to predict risk in a more proximate (5–10years)
period has proven to be more difcult. Clinical risk calculators have been developed, which incorporate a range of factors, including age, gender, cholesterol, additional lipid parameters (triglycerides, high-density lipoprotein cholesterol [HDL-C],
lipoprotein(a) [Lp(a)], blood pressure, diabetes, smoking, obesity and family history of premature atherosclerotic cardiovascular disease [2]. In general, where these
1].
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calculators determine a 10-year risk, they guide use of increasingly intensive therapy: lifestyle measures for those whose risk is less than 10%, intensive risk factor
modication where risk greater than 20% and more tailored therapy for those
between 10 and 20% [3].
However, the use of conventional risk prediction strategies in asymptomatic individuals has a number of challenges. They are derived from examination of large
populations and their ability to accurately predict in specic individuals is limited.
Some individuals determined to be low risk will experience clinical events, suggesting that other factors may underscore their atherosclerotic disease. Specic groups
associated with increased cardiovascular risk, including patients with genetic dyslipidaemia, systemic inammatory disease, human immunodeciency virus (HIV)
infection, end stage renal disease and indigenous populations [4–8], are not well
represented by these calculators and often require early use of intensive risk factor
modication. Patients with diabetes, for example, are considered a coronary risk
equivalent [9], and are triaged to intensive medical therapy in prevention guidelines.
These calculators estimate absolute risk yet provide no information with regard to
modiability of risk and cost effectiveness.
Development of a number of blood based and vascular imaging biomarkers have
been reported to provide incremental risk prediction in asymptomatic individuals
[10, 11], compared with conventional algorithms. While these have been incorporated into recent guidelines as adjunctive measures to predict risk [1], there have
been limited clinical trials performed to determine how to use these investigations
to optimise preventive therapies. The SCOT-HEART study has demonstrated that
use of computed tomography coronary angiography to detect plaque triages appropriate use of statin therapy and reduces cardiovascular events on long term follow
up [12]. In parallel, imaging studies may also play an important role in promotion
of adherence with medical therapies [13]. Ultimately, the use of risk prediction
strategies to tailor specic therapies to individual patients requires investigation in
order to develop precision medicine approaches to cardiovascular prevention.
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4.3 Lifestyle Measures
All approaches to the prevention of atherosclerotic cardiovascular disease should
involve a foundation of lifestyle measures. Despite reductions in age-related mortality with use of evidence-based therapies in developed nations, the global spread of
cardiovascular disease has resulted from an increase in obesity and associated metabolic risk factors, including early onset type 2 diabetes mellitus [14]. Accordingly,
increasing efforts are required to promote lifestyle measures for prevention of incident cardiovascular disease along the life course of the disease process [15].
Similarly, in patients with established disease, use of intensive risk factor modication agents does not justify a lack of attention to lifestyle measures.
Smoking is a highly preventable cause of cardiovascular disease. Mechanistic
studies have demonstrated a range of adverse effects on endothelial function,
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thrombosis, inammation and oxidative stress [16], which can be reversed with
smoking cessation [17, 18]. While public health measures have led to a reduction in
smoking rates in Western countries, there remains a considerable challenge worldwide [19]. A range of counselling and pharmacotherapy approaches have been
employed in smoking cessation strategies for individuals. The adverse cardiovascular effects of smoking have been extended to the setting of secondary exposure [20].
As a result, this needs to be considered in developing individual prevention plans.
The increase in abdominal adiposity highlights the need to address diet and exercise in all approaches for cardiovascular disease prevention. In addition to caloric
restriction, efforts to tailor dietary balance are of topical interest. Increasing consumption of highly processed foods, rich in carbohydrates, saturated fat and salt,
associate with risk factors and premature cardiovascular disease [21–23]. Evidence
that specic dietary interventions reduce cardiovascular events in large clinical trials in the contemporary era are lacking. Prevention guidelines, accordingly, emphasise a reduction in consumption of these dietary factors. In addition, 30–60min of
daily exercise have been demonstrated to have benets on risk factor control and
atherosclerotic plaque [24, 25], with no data to suggest incremental benet from use
of more intense or prolonged exercise regimens [26]. The potential for disease
reversibility with diet and exercise interventions appears to be greatest in adolescents, suggesting more modiable disease [27].
A. J. Nelson and S. J. Nicholls
4.4 Anti-platelet andAnti-thrombotic Therapies
The seminal event underlying most ischemic events involves the formation of
thrombus within the arterial lumen, secondary to either rupture or erosion of an
atherosclerotic plaque. Accordingly, major advances in the treatment of acute and
chronic ischaemic syndromes have been produced by the use of agents targeting
platelet function, the coagulation cascade or dissolution of established clot. Early
randomised controlled trials established that prompt administration of brinolytic
agents in the setting of acute arterial occlusion led to rapid reperfusion of vascular
territories and became standard of care for management of ST segment elevation
myocardial infarction [28]. In many centres with rapid access to cardiac catheterisation laboratories, primary percutaneous coronary intervention has subsequently
become the preferred treatment strategy for these patients [29]. Use of adjunctive
antiplatelet therapy, primarily with aspirin, has proven to reduce both early and long
term recurrent ischaemic events in patients with clinically manifest atherosclerotic
disease. More recent studies have demonstrated incremental clinical benet from
use of dual antiplatelet therapy, typically in the form of aspirin combined with clopidogrel, prasugrel or ticagrelor, in high risk patients for at least 12months after an
acute event [30–32]. Increasing evidence suggests ongoing benet with dual antiplatelet therapy beyond 12months and in more stable patients with high risk features, such as the presence of peripheral arterial disease [33, 34]. The use of
antiplatelet therapy in the primary prevention setting, however, appears to be less
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clear. Meta-analyses and the results of recent clinical trials have failed to demonstrate clear cardiovascular benet from widespread use of aspirin in patients without
symptomatic disease [35, 36]. At this point in time, it would seem that use of aspirin
for primary prevention is best reserved for specic high risk patients.
The use of anticoagulant therapy has evolved in the setting of atherosclerotic
disease [37]. While early administration of heparin either in its unfractionated or
low molecular weight formulations has been demonstrated to be efcacious as
adjunctive therapy in patients with acute ischaemic syndromes [38], longer term use
of warfarin has failed to produce consistent benet in clinical trials [39]. The development of more novel anticoagulant agents, which primarily target factor X, have
been increasingly used in combination with antiplatelet therapy in patients with
concomitant atrial brillation and atherosclerotic disease, by virtue of greater ease
of use compared with warfarin. Clinical trials have demonstrated these combinations to be highly effective and while associated with an increased risk of bleeding,
provide a useful therapeutic approach in the early setting following an acute ischemic event [40–42]. Recent studies have also demonstrated that administration of
low dose rivaroxaban reduced clinical events in patients with more stable, atherosclerotic disease [43], a benet which seemed to be greater in higher risk patients
such as those with manifest peripheral arterial disease [44]. While the mechanism
underlying this benet remains uncertain, the ndings do suggest that patients may
benet long term from use of anticoagulant therapy in addition to antiplatelet agents
to further reduce their risk of recurrent cardiovascular events.
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4.5 Blood Pressure Therapies
Hypertension is a highly prevalent and modiable risk factor, with evidence from
large population studies that the curvilinear increase in risk is observed at systolic
blood pressure levels within the range considered by many to be normal (i.e.
115mmHg) [45]. Randomised controlled trials performed over a number of decades
have conrmed that use of blood pressure lowering agents in patients with established hypertension, with systolic blood pressure levels greater than 160mmHg,
reduce cardiovascular event rates [46, 47]. This is further conrmed by metaanalyses which have demonstrated a linear relationship between both blood pressure lowering and achieved systolic blood pressure levels and cardiovascular benet
[48]. Accordingly, treatment guidelines for prevention of cardiovascular disease
recommend blood pressure lowering with the target largely determined by the overall level of cardiovascular risk of the patient. More recent updates to treatment
guidelines have advocated more intensive blood pressure lowering, aiming for a
level below 130/80mmHg in many higher risk patients [49]. To achieve such levels,
many patients will require use of multiple blood pressure lowering agents.
Conventional therapy often begins with use of either a calcium channel antagonist
or pharmacological inhibitor of the renin-angiotensin-aldosterone system, with
addition of the other class, beta-blockers or diuretics in combination. Patients with
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very high levels of blood pressure may also require use of more centrally acting
agents, although such patients are typically managed in specialist blood pressure
clinics. Particular attention in the setting of such high and refractory levels of hypertension should be paid to be possibility of underlying secondary causes (e.g. renal
artery stenosis, hyperaldosteronism, phaeochromocytoma, hyperthyroidism, kidney
disease, Cushing’s syndrome), which may require alternative interventions.
Additional approaches to management of refractory hypertension include the
potential to disrupt renal sympathetic nerve supply by use of radiofrequency ablation therapy [50]. While early studies of this catheter based approach to treatment of
patients with unacceptably high blood pressure levels, despite use of up to 4–5
agents, appeared promising with reports of effective blood pressure lowering when
measured in the clinic, this did not prove to be the case in either 24h blood pressure
monitoring or in a large, sham controlled clinical trial [51]. Ongoing efforts are in
progress to continue to advance effective approaches in this space in clinical studies.
There has also been considerable interest in the use of pharmacological agents to
delay or prevent the development of hypertension. This is based on observations
that cardiovascular risk begins to increase at levels not typically considered high
enough to warrant therapy and due to the natural history, in which blood pressure
tends to increase with age. While trials have demonstrated that early intervention
does reduce the progression to hypertension in this setting, the overall clinical
effect, both in terms of cardiovascular events and safety with the potential for symptomatic hypotension, remains uncertain. As a result, there is an ongoing need for
clinical trials to determine optimal blood pressure levels to commence therapy in
higher risk patients.
A. J. Nelson and S. J. Nicholls
4.6 LDL Cholesterol Lowering Therapies
Considerable evidence has implicated low-density lipoprotein cholesterol (LDL-C)
as a causal factor in atherosclerotic disease. Population studies demonstrate a curvilinear relationship between both LDL-C and apolipoprotein B (apoB) levels and
cardiovascular risk. Genetic studies have established that polymorphisms producing
lower LDL-C levels associate with less cardiovascular risk, the relationship being
proportional to the difference in apoB levels [52]. Monogenic states of hypercholesterolemia are well characterized by a greater incidence of premature cardiovascular
disease. Numerous clinical trials have established that lowering LDL-C with statins
favourably modies progression of atherosclerosis and reduces cardiovascular
events in the primary and secondary prevention setting [53, 54]. The degree of benet directly associates with the extent of LDL-C lowering and the greatest absolute
risk reduction is observed in those patients at highest baseline risk of experiencing
a cardiovascular event. While posthoc analyses of statin trials demonstrated an independent association between lowering of the inammatory marker, C-reactive protein (CRP), and benet, suggesting potential pleiotropic effects, the clinical
signicance remains uncertain [55]. This may contribute to ndings that high
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intensity statin therapy has an early clinical benet in patients with acute coronary
syndromes, which has provided the evidence for guideline-based management in
the hospital setting.
However, a number of challenges remain despite the widespread use of statins
for prevention of atherosclerotic cardiovascular disease. A substantial residual risk
of clinical events is observed, even in patients treated with high intensity statin
therapy or achieving current guideline targets. This suggests that additional strategies, including greater lowering of LDL-C, may be required in these patients. Many
patients, particularly those with genetic hypercholesterolemia or those unable to
tolerate high statin doses, are unable to attain treatment goals. These factors, in
addition to reductions in adherence on long term follow up, will contribute to ongoing cardiovascular risk in patients and the need to develop new lipid lowering therapies [56].
Ezetimibe is a cholesterol absorption inhibitor, which lowers LDL-C by 15–20%
as monotherapy or in combination with statins. Clinical trials have demonstrated
that when used in combination with statins, ezetimibe produces incremental plaque
regression [57] and reductions in cardiovascular events [58]. Proprotein convertase
subtilisin/kexin type 9 (PCSK9) plays an important role in regulation of LDL-C,
through its role in degradation of the LDL receptor in the liver. Gain of function
PCSK9 mutations have been identied in some patients with familial hypercholesterolemia, while loss of function polymorphisms have been demonstrated to associate with lower levels of both LDL-C and cardiovascular risk. Development of
monoclonal antibodies, administered subcutaneously every 2–4weeks, has been
demonstrated to be well tolerated, to lower LDL-C by up to 60% on top of statin
therapy and reduce cardiovascular event rates in large clinical trials. The clinical
benet of these agents appears to be greatest in patients with either the highest
baseline LDL-C levels or those at highest risk of future cardiovascular events,
including those with atherosclerosis involving multiple vascular territories, multivessel coronary disease and recurrent ischaemic events [59]. Given the high cost of
these agents, considerable efforts are underway to determine how to optimally
triage their use to patients where their cost effectiveness will be greatest. Alternative
approaches to PCSK9 inhibition involve impairing RNA synthesis within the liver,
which will enable more durable biochemical effects and potentially much less frequent administration. Clinical trials of the RNA inhibitor, inclisiran, administered
twice yearly are currently in progress to determine its clinical efcacy and safety
[
60]. An additional oral agent, bempedoic acid is being developed primarily for
patients with statin intolerance. This agent reduces cholesterol biosynthesis in the
liver, in a manner similar to statins, yet is not biologically active within muscle and
theoretically may produce less myalgia, which can be problematic for many statintreated patients. While the degree of LDL-C lowering is relatively modest
(15–25%) [61], when combined with ezetimibe and potentially low doses of
statins, this agent may have the potential to produce highly effective LDL-C reductions. The clinical efcacy and safety of bempedoic acid is currently being investigated in a large clinical trial of high cardiovascular risk patients with established
statin intolerance.
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A. J. Nelson and S. J. Nicholls
4.7 Additional Lipid Modifying Therapies
While a generation of clinical development has produced a range of cardioprotective agents targeting LDL-C, there continues to be interest in use of therapies that
modulate other circulating lipoproteins. Population and animal studies have suggested that high-density lipoproteins (HDL) are protective [62]. Accordingly, there
has been considerable interest in development of HDL raising agents [63]. However,
multiple clinical trials involving novel formulations of niacin and cholesteryl ester
transfer protein (CETP) have proven to be disappointing, despite substantial HDL-C
elevation [64]. This is supported by observations from genetic studies that polymorphisms that produce differences in HDL-C levels do not associate with alterations
in cardiovascular risk. In contrast, multiple studies have suggested that the functionality of HDL, as opposed to quantitative measures of its cholesterol content, may be
a more important determinant of cardiovascular risk. This is evidenced by reports
that greater exvivo cholesterol efux capacity associates with protection from incident cardiovascular events [65]. Trials utilising HDL infusions, which stimulate
cholesterol efux, without any discernible long term increase in HDL-C levels, have
proven to exert variable effects on plaque and are currently being investigated for
their impact on cardiovascular events [66].
In parallel, the role of triglyceride rich lipoproteins (TRLs) in cardiovascular
disease has varied. Contemporary analysis on the basis of both population and
genetic studies implicates TRLs in the causal pathway for atherosclerosis. This is
particularly important as hypertriglyceridemia is highly prevalent in the settings of
abdominal obesity and type 2 diabetes, with elevations in both fasting and postprandial TRL levels. In the absence of evidence that triglyceride lowering results in
cardiovascular protection, treatment guidelines have largely focused on use of more
intensive LDL-C lowering strategies in the patient with hypertriglyceridemia. A
number of observations provide some insight for use of approaches beyond LDL-C
lowering in the patient with elevated triglyceride levels. Fibrates have a range of
effects including lowering of triglycerides and LDL-C and elevation of HDLC.While agents have produced variable effects on cardiovascular events in large
outcomes trials, meta-analyses have demonstrated that any potential benet of these
agents is predominantly observed in the patient with baseline hypertriglyceridemia
[67]. This has prompted the design of clinical trials that specically target high risk
patients with elevated triglyceride levels. Administration of high dose omega-3 fatty
acids, in the form of eicosapentaenoic acid, has been demonstrated to reduce cardiovascular event rates in patients with hypertriglyceridemia at study entry [68]. This
nding contrasts with prior data of omega-3 fatty acids, in which administration of
low doses that failed to substantially elevate tissue levels, to patients with normal
triglyceride levels, did not reduce cardiovascular risk. Ongoing studies of other
omega-3 fatty acid preparations [69] and selective peroxisome proliferator activated
receptor modulators in similar patients will determine whether a number of strategies will be effective when tailored to patients with a specic atherogenic dyslipidemia phenotype. Future studies of agents targeted to inhibit factors that impair
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metabolism of TRLs will determine whether directly lowering triglyceride levels
will be atheroprotective.
Lipoprotein (a) [Lp(a)] has received increasing attention as an individual lipid
target in cardiovascular prevention [70]. This atherogenic lipoprotein has a structure
including an apoB particle bound to apo(a) with considerable homology to plasminogen. Accordingly, this lipoprotein is thought to play an important role in atherogenesis, calcication and thrombosis. Lp(a) levels are genetically regulated with
increasing evidence from Mendelian randomization studies that Lp(a) plays a causal
role in both atherosclerotic disease and calcic aortic stenosis [71]. While statins do
not lower Lp(a) and in some cases can increase its levels, use of high intensity statin
therapy is advocated in high risk patients with elevated Lp(a) levels in efforts to
reduce LDL-C levels as low as possible. Existing therapies that lower Lp(a) include
niacin and oestrogen, although these agents have failed to produce cardiovascular
benet in contemporary clinical trials. PCSK9 inhibitors lower Lp(a) by up to 30%,
with some evidence that this contributes to their cardiovascular benet [72].
However, increasing interest has focused on the development of specic therapies
that reduce Lp(a) synthesis, with several of these agents proceeding in clinical
development. Given the role of Lp(a) in risk stratication and additional ability to
identify patients with familial hypercholesterolemia, there is increasing support for
widespread measurement of Lp(a) levels in clinical practice, in order to determine
which patients require more aggressive risk factor modication.
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4.8 Glucose Lowering Therapies
With an increasing prevalence of obesity, type 2 diabetes has become a global
public health challenge and is a major factor underscoring the worldwide spread of
premature cardiovascular disease. In addition to its high prevalence in patients
with manifest atherosclerotic disease, the presence of diabetes associates with
adverse outcomes and the presence of diffuse, systemic atherosclerotic disease
[14]. Despite the clear association between dysglycaemia and cardiovascular risk
[73], clinical trials of glucose lowering therapies for decades failed to demonstrate
macrovascular benet. With reports of potential cardiovascular harm with the
PPAR-γ agonist, rosiglitazone, the regulatory requirements for approval of novel
glucose lowering agents has changed, with the need to demonstrate cardiovascular
safety in larger trials. This has paved the way for a large number of clinical trials
of agents, which not only have proven to be safe, but have nally demonstrated
cardiovascular benet.
The sodium glucose cotransporter-2 (SGLT2) inhibitors act primarily via urinary
excretion of excess glucose and are highly effective at improving glycaemic control
in the setting of type 2 diabetes. Large outcomes trials of three agents have demonstrated cardiovascular benet [74]. While the benets in these trials have variably
involved mortality, heart failure and atherosclerotic specic events, the reduction in
uid volume and improvement in cardiac dimensions suggests that this may be the
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major mechanism underlying their benet. This is being directly tested in the settings of heart failure with either reduced or preserved ejection fraction. Additional
data has subsequently reduced progression to adverse renal outcomes, suggesting
widespread benet [75]. Caution should be taken in patients with a history of recurrent urinary or genital tract infection and a small, but signicant increase in the rate
of ketoacidosis and in the case of canagliozin, lower limb amputations, has been
reported. The latter suggests that caution should be taken with use of these agents
with prior amputation or severe small vessel disease involving the extremities.
Glucagon-like peptide-1 (GLP-1) receptor agonists have also been demonstrated
to improve glycaemic control, in addition to promoting weight loss by up to 10%,
when administered via subcutaneous injection. Cardiovascular outcomes trials have
demonstrated a reduction in clinical events with a number of these agents [76]. The
major tolerance issue observed with these agents involves the development of nausea. More recent developments include the ability to administer GLP-1 receptor
agonists orally and in combination with glucose-dependent insulinotropic polypeptide receptor agonists, the latter having the potential to achieve profound lowering
of glycated haemoglobin by more than 2% [77]. The clinical impact of these
advances remain to be determined in large clinical trials. As a result of these ndings, treatment guidelines for management of high-risk atherosclerotic disease
patients with type 2 diabetes advocates use of additional glucose lowering agents
(preferentially SGLT2 inhibitors or GLP-1 receptor agonists given their cardiovascular benet) in combination with background metformin in patients with glycated
haemoglobin levels greater than 7% [78]. Whether administration of these agents
will produce cardiovascular benet when used in patients with better glycaemic
control remains to be determined.
A. J. Nelson and S. J. Nicholls
4.9 Anti-Inammatory Therapies
Increasing evidence implicates inammation at all stages of the atherosclerotic disease process. This is supported by mechanistic observations of plaque formation,
progression and rupture and reports that greater circulating levels of inammatory
markers associate with prospective cardiovascular risk. The report that lowering
C-reactive protein (CRP) levels independently associates with the benets of statins
suggests that anti-inammatory properties may contribute to their cardiovascular
benet. As a result of these ndings, considerable efforts have been undertaken to
develop novel therapeutic approaches that primarily target the inammatory nature
of atherosclerosis. Early studies that have targeted specic downstream mediators
of inammation (phospholipase inhibitors, lipoxygenase inhibitors) have failed to
reduce cardiovascular event rates or favourably modulate atherosclerotic plaque.
More recent efforts with agents that target the role of the inammasome, a more
upstream coordinator of the inammatory cascade within the artery wall, have
yielded promising results. A small study of patients with stable coronary artery disease demonstrated a clinical benet with administration of low-dose colchicine [79].
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