REVIEWS

Treatment of refractory angina in patients

notsuitable for revascularization
Timothy D. Henry, Daniel Satran and E. Marc Jolicoeur
Abstract | A growing number of patients, particularly those with advanced, chronic coronary artery disease,
experience symptoms of angina that are refractory to treatment with blockers, calcium-channel blockers,
and long-acting nitrates, despite revascularization. The management of patients with refractory angina who
are unsuitable for further revascularization is strikingly different across the world, and is contingent on local
resources and available expertise. Mortality in this patient population has decreased, but enhancing quality
of life remains a challenge. New treatment principles are emerging in current practice, such as metabolic
modulation, therapeutic angiogenesis, and novel interventional techniques (coronary in-flow redistribution
and approaches to chronic total occlusion). The contemporary management of refractory angina encourages
individualized, patient-centred care in interdisciplinary, specialized clinics. Global initiatives are required
to address complex clinical problem-solving for patients with refractory angina. In this Review, we discuss
the epidemiology of refractory angina, and provide an update on the pharmacological, noninvasive, and
interventional options that are available to these patients or are under development.
Henry, T. D. etal. Nat. Rev. Cardiol. 11, 7895 (2014); published online 24 December 2013; corrected online 14 January 2014;
doi:10.1038/nrcardio.2013.200

Introduction
An increasing number of patients, particularly those
with advanced, chronic coronary artery disease (CAD),
have severe symptoms of angina despite optimal medical
therapy. When further revascularization options are
limited, these patients are frequently described as being no
option, and as having refractory angina.16 The care of these
patients is challenging, and the guidance available from
national practice guidelines is limited.4,68 Over 10years
ago, the ESC Joint Study Group on the Treatment of
Refractory Angina defined this condition as a chronic con-
dition (3months) characterized by the presence of angina
caused by coronary insufficiency in the presence of CAD,
which is not amenable to a combination of medical therapy,
Cedars-Sinai Heart angioplasty, or coronary bypass surgery in patients with
Institute, 127 South
San Vicente Boulevard,
evidence of ischaemia.3 Patients can be suboptimal can-
AHSP, A3100, Los didates for revascularization for many reasons, includ-
Angeles, CA90048, ing having unsuitable coronary anatomy (severe diffuse
USA (T. D. Henry).
ParkNicollet Heart atherosclerosis, or the absence of targets or lack of graft
andVascular Center, conduits for CABG surgery), the presence of substantial
6500 Excelsior
Boulevard, StLouis
comorbidities (severe left ventricular dysfunction, periph-
Park, MN55426, USA eral artery disease, or chronic kidney disease), or because
(D.Satran).
Department of
Medicine, Montreal
Heart Institute, Competing interests
Universit de Montral, T.D. Henry declares associations with the following companies
5000 Belanger East
and organizations: Abbott Vascular, Baxter, Cytori, Gilead,
Street, Montreal, Neovasc, and the NIH Cardiovascular Cell Therapy Research
Qubec H1T1C8,
Network. E.M. Jolicoeur declares associations with the following
Canada
(E.M.Jolicoeur).
companies and organizations: Baxter, the Canadian Institutes
forHealth Research, la Fondation de lInstitut de Cardiologie de
Montral, les Fonds la Recherche du Qubec en sant, Gilead,
Correspondence to:
T. D. Henry Neovasc, and Servier. See the article online for full details of
timothy.henry@cshs.org therelationships. D. Satran declares no competing interests.
of advanced age. The term refractory anginacan also
encompass patients with microvascular angina and less-
extensive CAD. We previously described a classification
scheme to help to characterize this complex population
of patients.5 The interaction between clinical symptoms,
myocardial perfusion abnormalities (or lack thereof), and
coronary anatomy is complicated in these individuals.4,5,7,8
In this Review, we discuss the epidemiology of refractory
angina, and provide an update on the pharmacological,
noninvasive, and interventional options that are available
to these patients or are underdevelopment.
Epidemiology
With only limited data available from small, observa-
tional studies, the ESC Joint Study Group recognized an
urgent need to clarify the epidemiology of this condition
[refractory angina].3 The Joint Study Group estimated
the incidence of refractory angina at between 5% and
10% of patients undergoing cardiac catheterization.3 On
the basis of coronary anatomy, symptoms, and myocardial
perfusion, the incidence of patients with no option was
11.8% in a series from the 1990s.9 In a subsequent series,
29% of 493 consecutive patients undergoing cardiac cath-
eterization had incomplete revascularization, including
16% of patients who were not candidates for revascular
ization.10 No data are available from national registries,
such as Medicare; no specific claims codes exist for this
complex group of patients, and standardized definitions
are challenging. Currently, >500,000 Canadians and up
to 1.8million individuals from the USA are estimated to
have refractory angina.4

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Key points
Refractory angina is an increasingly prevalent clinical syndrome characterized
by ongoing ischaemic symptoms despite optimal medical management in
patients for whom traditional revascularization is not an option
Data indicate that up to 1015% of patients undergoing cardiac catheterization
fit the clinical description for refractory angina, and that prognosis is improving,
with an annual mortality of only 34%
The primary focus is on improving quality of life for patients with refractory angina
Traditional treatment for myocardial ischaemia involves increasing coronary
blood in-flow, increasing blood oxygen-carrying capacity, and decreasing oxygen
consumption; new treatments involve modulating myocyte metabolism and
redistributing coronary flow
Emerging therapies include novel interventional techniques (percutaneous
coronary intervention for chronic total occlusions, and the coronary
sinus occluder), angiogenesis with cell therapy, shockwave therapy, and
neuromodulation
Implementation of interdisciplinary, specialized clinics with advanced clinical
care, as well as investigational options (including psychological and self-
management approaches), could be important advances for patients with
refractory angina
Box 1 | Summary of practice guidelines for refractory angina
Novel pharmacological agents
The ESC guidelines now consider ivabradine, nicorandil, or ranolazine on a par
with long-acting nitrates as a second-line therapy for patients with persistent
angina, according to heart rate, blood pressure, and tolerance (classIIa, level of
evidenceB).8 Trimetazidine is also recommended as a second-line therapy, but its
use is less well established (classIIb, level of evidenceB).8
The US guidelines consider ranolazine useful when prescribed as a substitute
for blockers for relief of symptoms in patients where the initial treatment with
blockers led to unacceptable adverse effects, or was ineffective, or if initial
treatment with blockers is contraindicated (classIIa, level of evidenceB).7
Ranolazine can be used in combination with blockers when prescribed for relief
of symptoms when initial treatment with blockers is not successful (classIIa,
level of evidenceA).7 Ivabradine, nicorandil, and trimetazidine are not available
inthe USA and are not addressed in the practice guidelines.7
The Canadian guidelines put an emphasis on the need for robust randomized,
controlled trials focusing on patients with refractory angina before ivabradine,
nicorandil, ranolazine, and trimetazidine can be definitively recommended in
patients with refractory angina.4
Invasive treatment
The Canadian and US guidelines weakly support the use of PMLR for reduction
in the perceived severity of angina pain symptoms (weak recommendation with
moderate-quality evidence,4 and classIIb, level of evidenceB,7 respectively).
The ESC guidelines do not support the use of PMLR or transmyocardial laser
revascularization (classIII, level of evidenceB).8
According to all three practice guidelines, spinal-cord stimulation can be
considered for reducing the perceived severity of angina pain symptoms and for
improving exercise capacity (classIIb, level of evidenceB; weak recommendation
in both instances with moderate-quality evidence).4,8,7
Noninvasive treatment
The Canadian and US guidelines propose that EECP can be considered to improve
quality of life and severity of angina symptoms (weak recommendation with
low-quality evidence,4 and classIIb, level of evidenceB,7 respectively), whereas
the ESC guidelines support the use of EECP for symptom relief in patients with
refractory angina (classIIa, level of evidenceB).8
According to the Canadian guidelines, patient self-management training can
be considered for the reduction of angina symptoms and associated use
of sublingual nitrates, and to improve health-related quality of life (weak
recommendation, moderate-quality evidence).4
Abbreviations: EECP, enhanced external counterpulsation; PMLR, percutaneous myocardial
laser revascularization.
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REVIEWS
Data on prognosis in refractory angina are conflicting.
In a study from the 1990s, 1year mortality was 16.9%,
but was calculated on the basis of only 59 patients.11
A wide range of 1year mortality figures (122%) has
been reported from randomized clinical trials involving
patients with refractory angina.1219 Contemporary data
on 1,200 patients from a specialized refractory angina
clinic at the Minneapolis Heart Institute, MN, USA is
much more encouraging, with a mortality of 3.9% at
1year and 28.4% at 9years.20
Survival with refractory angina seems to have improved
over time, which is likely to be a result of the widespread
adoption of standard medical therapy, aggressive risk-
factor modification, and innovative revascularization
techniques. Systematic evaluation in a specialized clinic
might also improve long-term outcome. With improved
survival, quality of life becomes the focus of therapy.
Evaluation of novel therapies
Designing clinical trials to evaluate therapeutic options
in patients with refractory angina is challenging. The
cyclical nature of angina, combined with a prominent
placebo effectparticularly for invasive therapies (such
as transmyocardial laser revascularization, spinal-cord
stimulation [SCS], or novel revascularization techniques),
which cannot easily be placebo-controlledhas led to
scepticism and low rates of uptake. Few treatments for
refractory angina achieve a strong recommendation when
assessed using contemporary level-of-evidence meas-
ures.21 Novel therapies have been developed, but despite
their initial promise, placebo-controlled trials have shown
only modest improvements in exercise treadmill time
and symptoms of angina. Prominent placebo effects have
obscured results from potentially innovative approaches
and must be taken into consideration when discussing the
beneficial effects of novel therapies. In the 2012 Canadian
Cardiovascular Society (CCS) practice guidelines for the
management of patients with refractory angina, all non-
pharmacological options received a weak recommend
ation for use (Box1).4 The majority of novel antianginal
treatments have been studied in patients with stable CAD,
rather than formally evaluated in patients with advanced
CAD that is refractory to conventional therapy.1,2
Angina is traditionally treated with risk-factor modi-
fication and antianginal medications, as well as revas-
cularization by percutaneous coronary intervention
(PCI) or CABG surgery. Improved understanding of
myocardial ischaemia has led to new therapeutic prin-
ciples, including metabolic modulation, oxygen sparing,
and coronary flow redistribution (Figures1 and 2). To
manage these challenging patients successfully, clin
icians must address the ischaemic component of angina,
as well as other factors in dynamic cardiac pain, such as
the neurogenic or psychogenic components.
Novel pharmacological agents
The mainstay of medical treatment for angina involves
blockers, long-acting nitrates, and calcium-channel
blockers. These traditional antianginal agents exert their
effect by reducing heart rate, myocardial contractility,
REVIEWS

Intermittent FiO2 Hb Allopurinol Trimetazidine Perhexiline

thrombolytics

Oxidative stress 3-KAT CPT1/2

reduction inhibition inhibition

Blood rheology O2-carrying capacity O2 sparing Metabolic modulation

Coronary flow Ranolazine

redistribution
Supply Demand
Coronary sinus
reduction INa inhibition

Coronary blood in-flow Heart rate

? Contractility
LV wall tension
?
Angiogenesis
Cell therapy Nitrates Calcium-channel
Nitrates
Gene therapy EECP PCI CABG surgery Nicorandil -Blockers Ivabradine blockers
Nicorandil

Figure 1 | Therapeutic principles of myocardial ischaemia. The classic treatment of myocardial ischaemia has
traditionallyrelied on three principles: reduction in LV oxygen consumption, augmentation of coronary arterial blood in-
flow, and maximized oxygen-carrying capacity of the blood. Novel therapies and devices have allowed refinement of these
principles and the rise of novel treatment strategies, such as oxygen sparing, metabolic modulation, and redistributing
the coronary blood flow. Nonpharmacological options are displayed in blue boxes, whereas pharmacological therapies
are displayed inyellow boxes. Abbreviations: 3KAT, mitochondrial long-chain 3ketoacylCoA thiolase; CPT1/2, carnitine
Opalmitoyltransferase1 and 2; EECP, enhanced external counterpulsation; FiO 2, fraction of inspired oxygen; Hb,
haemoglobin; LV, left ventricular; PCI, percutaneous coronaryintervention.

and blood pressure; all can be useful in patients with
refractory angina.1,4,68
Blockers have historically been favoured over calcium-
channel blockers in patients unsuitable for revascular
ization, because these individuals have often previously
had a myocardial infarction (MI; blockers reduce mor-
tality after MI7) and have reduced left ventricular func-
tion (nondihydropyridine calcium-channel blockers have
been associated with increased mortality in the setting of
low left ventricular ejection fraction7). The dominance
ofthese traditional agents has been questioned,22 and treat-
ment of chronic stable angina is slowly moving beyond
these drugs. The ESC and the National Institute for Health
and Care Excellence in the UK now advocate the use of
ivabradine, nicorandil, or ranolazine with the same level
of recommendation as monotherapy with long-acting
nitrates or in association long-acting nitrates, when neither
blockers nor calcium-channel blockers can be adminis-
tered.6,8 Therapeutic choice is dependent on comorbidities,
accessibility, costs, and potential adverse effects.1,4,68
To be clinically useful, alternative antianginal agents
must be safe and effective in patients receiving traditional
medical therapy. Many of the novel agents have limited
negative chronotropic and hypotensive effects and are,
therefore, appropriate for patients who do not tolerate
traditional antianginal drugs for these reasons (Table1).
Nicorandil
Nicorandil is a nicotinamide ester comprising a nitrate-
like moiety, which vasodilates coronary arteries, and a
cardioprotective moiety, which promotes the opening
of the mitochondrial ATP-sensitive potassium chan-
nels (KATP), known to mimic ischaemic preconditioning
(Figure3).23 The results of the IONA trial24 demonstrated
the cardioprotective effect of nicorandil among patients
withchronic stable angina, with a reduction com-
paredwith placebo in the combined end point of cardio
vascular death, nonfatal MI, and hospital admission
for cardiac chest pain (13.1% versus 15.5%; P=0.014).
Nicorandil exerts an anti-ischemic effect similar to that
of blockers, calcium-channel blockers, and long-acting
nitrates in patients with stable angina that occurs with
physical exercise.23,2529 Nicorandil has never been studied
in patients with advanced CAD, where cardioprotective
and antianginal effects might be most pronounced.
Nicorandil seems particularly appealing as a substitute
for long-actingnitrates, which can be associated with
tachyphylaxis and tolerance. Nicorandil neither impairs
endothelial function nor paradoxically exacerbates
angina,30 as is often the case with long-acting nitrates.31
Nicorandil is available in Europe, but its availability is
restricted by special-access programmes run by regulatory
agencies in Canada and the USA.
Ivabradine
Ivabradine has been shown to be noninferior to blockers
in reducing the number of angina attacks in patients with
chronic stable angina.32 Ivabradine blocks If channels,
which regulate the intrinsic chronotropic characteristics
of the sinoatrial node. Unlike calcium-channel blockers
and blockers, ivabradine does not reduce blood pressure
or exert negative bathmotropic or dromotropic effects.

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 REVIEWS

Narcotics

Transplantation Experimental
and palliative
Angiogenesis options

ESWT, sinus reduction

O2 sparing: allopurinol

Self-management training
Nonpharmacological: EECP, SCS, TMLR Therapies for
refractory angina
Metabolic modulation: trimetazidine, perhexiline (?)

Late Na current inhibition: ranolazine

Coronary blood flow increase: PCI, CTO PCI, CABG surgery

Evidence-based
Coronary vasodilatation: nitrates, nicorandil, molsidonine (?) therapies for
stable angina
Heart rate and contractility reduction: -blockers, calcium-channel blockers, ivabradine

Treat hypertension, diabetes mellitus, dyslipidaemia

Risk-factor
Smoking cessation, regular exercise and rehabilitation, healthy lifestyle reduction

Figure 2 | Treatment options for refractory angina. The treatment of refractory angina starts with the management of risk
factors (yellow steps) and the implementation of evidence-based therapy for chronic stable angina (pink steps). Available
options for refractory angina include medical therapies and devices (green steps). The blue and orange steps display
experimental and palliative options, which should be considered after lower options have been attempted. Abbreviations:
CTO, chronic total occlusion; EECP, enhanced external counterpulsation; ESWT; extracorporeal shockwave therapy; PCI,
percutaneous coronary intervention; SCS, spinal-cord stimulation; TMLR, transmyocardial laser revascularization.

Inaddition to heart-rate reduction, ivabradine might
allow vasodilatation beyond that achieved by blockers,
possibly through unmasked adrenergic vasoconstric-
tion in the coronary circulation.33 In the ASSOCIATE
trial,34 889 patients with stable angina despite taking
atenolol 50mg daily were randomly allocated to either
ivabradine up to 7.5mg twice daily or placebo for
4months. Total exercise time increased by 24.365.3s
with ivabradine, compared with 7.763.8s with placebo
(P<0.001).34 In the randomized BEAUTIFUL trial, 35
ivabradine did not improve cardiovascular outcomes for
patients with left ventricular systolic dysfunction and
stable CAD. However, in the subgroup of patients with
limiting angina at baseline, ivabradine was associated
with a 24% reduction in cardiovascular death and hos-
pitalization for MI or heart failure (HF).36 Rates of use of
blockers and long-acting nitrates in the substudy were
high (90% and 74%, respectively), which mirrors therapy
for many patients with refractoryangina.
Ivabradine might be useful in patients with refractory
angina who do not tolerate high doses of blockers, or
when calcium-channel blockers are contraindicated.
Ivabradine does not exert an antihypertensive effect and
can be considered when orthostatic or relative hypo
tension is a concern, particularly when optimal heart-rate
lowering (<70bpm) is not achieved.34 In HF, ivabradine is
particularly attractive, because the drug has been shown
to reduce all-cause mortality and the rate of adverse
clinical outcomes.37 Ivabradine has limited a vailability in
North America, but is widely used in Europe.
Ranolazine
Ranolazine affects ion channels in cardiomyocytes
similarly to amiodarone,38 mainly via inhibition of late
sodium currents (Figure3).39 The mechanisms of the
anti-ischaemic and antianginal effects of ranolazine are
debated, but might involve partial inhibition of fatty-
acid oxidation. Ranolazine has also been suggested to
improve regional coronary in-flow in areas of myo
cardial ischaemia.40 Ranolazine improves total exercise
time and ischaemic threshold in patients with chronic
stable angina.4143 In the CARISA trial,42 ranolazine in
combination with either amlodipine, atenolol, or diltia
zem increased treadmill exercise capacity and reduced
angina and nitroglycerin use, compared with placebo. In
patients with refractory microvascular angina (abnormal
exercise stress test, normal coronary arteries, and coro-
nary flow reserve <2.5), both ranolazine (375mg twice
daily) and ivabradine (5mg twice daily) were superior to
placebo for improving angina-related quality of life.44,45
In patients with type2 diabetes mellitus and chronic
stable angina despite the use of up to two antianginal
agents, ranolazine was superior to placebo in reducing
the weekly angina frequency (3.8 versus 4.3 episodes;
P=0.008) and sublingual nitroglycerin use (1.7 versus
2.1 doses; P=0.003).46 Ranolazine is currently being
compared with placebo in patients with chronic angina
who undergo PCI with incomplete revascularization, to
assess its efficacy in reducing major cardiac events and
improving angina-related quality of life.
Ranolazine has never been tested in a specific trial of
patients with refractory angina, but registry data suggest
effectiveness in this population.47 The safety of ranolazine
is well established, including for patients with an acute
coronary syndrome.48 Ranolazine does not affect heart
rate or blood pressure and might also have antiarrhythmic
properties, but is frequently associated with adverse
effects, including dizziness and headaches, particularly at
the maximal recommended dose (1,000mg twice daily).
Ranolazine is available in the USA and Europe.

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REVIEWS
Table 1 | Pharmacological therapies for refractory angina
Pharmacological Proposed mechanism of action
agent
Oxygen-sparers
Allopurinol Inhibits xanthine oxidase and its associated
oxidative stress, which prevents oxygen
wastage,endothelial dysfunction, and
substratedepletion.50,52
Late Na+ current inhibitors
Ranolazine Inhibits late inward Na+ current, which prevents
Ca2+ overload and increased diastolic tension
(which impairs coronary perfusion).39
Improves regional coronary blood flow in areas
ofmyocardial ischaemia.40
Might partially inhibit mitochondrial fatty-acid
oxidation (controversial at clinical doses).
Partial fatty-acid oxidation inhibitors
Perhexiline Inhibits carnitine Opalmitoyltransferase1 and 2,
which transfer free fatty acid from the cytosol
intomitochondria.60
Trimetazidine Reversibly inhibits mitochondrial long-chain
3ketoacylCoA thiolase, an important enzyme
infatty-acid oxidation in mitochondria.55
Vasodilators
lArginine Improves coronary blood flow via nitric-oxide-
mediated, endothelium-dependent vasodilatation.64
Fasudil and Inhibit Rho kinase, which possibly reduces
hydroxyfasudil calcium sensitization of vascular smooth
muscle150 to maintain coronary vasodilatation
andprevent vasospasm.151
Molsidomine Direct nitric oxide donor (sydnonimine), which
vasodilates the coronary vasculature.
Nicorandil Nitrate-like effect that vasodilates the coronary
vasculature and venous system
Cardioprotective effects, presumably through
opening of mitochondrial ATP-sensitive
potassiumchannels.154
If channel blockers
Ivabradine If channels blockers reduce the automaticity of
spontaneous depolarization in the sinoatrial node
cells, with resultant bradycardia.156
Possible vasodilatory effect when used instead
ofblockers.33,157
Antidepressants
Escitalopram SSRIs targeted at reducing the effect of mental
stress-induced haemodynamic response,143 such as
coronary artery vasoconstriction and microvascular
changes, along with metabolic risk factors.158
SSIRs are inhibitors of the 5hydroxytryptamine
platelet receptor, which reduces platelet
aggregation.159
Imipramine Tricyclic antidepressant thought to exert an
analgesic effect on the visceral component
associated with cardiac pain.
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Comments
Allopurinol has not been shown to improve symptoms or
toprevent major adverse cardiac events. Despite the wide
availability of the drug, its use at the high doses described
in clinical trials should remain investigational until
additional safety data are available.50,51
Ranolazine exerts a dose-dependent prolongation of the
QT interval. The FDA recommends restricting its use to
patients with persistent symptoms despite adequate
doses of evidence-based therapies.
Inadequately investigated in patients with ischaemic heart
disease. Growing clinical experience in patients with
congestive heart failure. Plasma concentration required for
dose titration.
Chronic trimetazidine use has been associated with
extrapyramidal adverse reactions, including Parkinsonism,
gait disorders, and restless leg syndrome.149
Inadequately investigated in patients with ischaemic heart
disease.
Have shown anti-ischaemic, but no antianginal, effects
inpatients with151 or without150 concomitant antianginal
medication. Currently available in Japan for prevention
ofcentral nervous system vasospasm associated with
subarachnoid haemorrhage. Potentially useful for
vasospastic angina.
In a double-blind, randomized, controlled trial (n=533),
molsidomine was superior to placebo for reducing the
incidence of angina and the use of sublingual nitrate
tablets, with no apparent development of tolerance.152
The effect of molsidomine on major adverse cardiac
events has not been adequately investigated.153
Acceptable substitute for long-acting nitrates when nitrate
tolerance is a concern; not associated with impaired
endothelial function during chronic use.30 Nicorandil has
been associated with anal ulceration.155
In patients with ischaemic cardiomyopathy and congestive
heart failure, ivabradine was associated with a 24%
reduction in the occurrence of cardiovascular death and
hospitalization for myocardial infarction or heart failure.35
In 15% of patients, ivabradine was associated with
headache, dizziness, and brightness in the visual field.
Escitalopram exerts its anti-ischaemic effects independently
of any effects it might have on symptoms of depression.143
The effect of escitalopram on angina symptoms remains
unknown. MSIMI is typically without pain and occurs with
lower levels of oxygen demand than exercise-induced
ischaemia. Escitalopram is associated with an increased
risk of suicide in particular subsets of patients.
Historical interest. Investigated in patients with cardiac
pain and a normal coronary angiogram, and was shown to
improve symptoms,160 but not quality of life.161
Inadequately studied in patients with advanced CAD and
refractory angina.

Table 1 (Cont.) | Pharmacological therapies for refractory angina
Pharmacological Proposed mechanism of action
agent
Chelation therapy
EDTA (associated Mechanism of action uncertain, possibly
with various associated with reduced oxidation of low-density
vitamins) lipoprotein,162 vasodilatory effects,163 and
enhanced production of tissue plasminogen
activator.149
Rheological agents
Intermittent Depletion of plasma fibrinogen, which reduces
thrombolytics blood viscosity and improves the rheological
(urokinase) properties of blood in the microcirculation.67,164,165
Testosterone
Testosterone Promotes endothelium-dependent relaxation of
coronary arteries.
Abbreviations: CAD, coronary artery disease; EDTA, ethylenediaminetetraacetic acid; MSIMI, mental stress-induced myocardial ischaemia; SSRI, selective
serotonin-reuptake inhibitor.
Allopurinol
Allopurinol, a well-accepted therapy for gout, reduces oxi-
dative stress mediated by xanthine oxidase (Figure3).49,50
By inhibiting oxidative stress, allopurinol increases the
level of oxygen available to transform fatty acids and
pyruvate into energy. Allopurinol has also been shown
to mediate an improvement in endothelium-dependent
vasodilatation in patients with CAD 51 or HF. 52 In a
small trial involving 65 patients with stable angina (87%
taking blockers), allopurinol 300mg twice daily was
superior to placebo in prolonging time to both chest pain
(+43s,95%CI 3158s) and STsegment depression (+58s,
95%CI 4577s), but the trial was not powered to detect
a difference in angina burden, quality of life, or clinical
outcomes.53 Larger trials are needed to test this benefit.
Trimetazidine
Trimetazidine is a metabolic agent that increases
glucose oxidation, possibly by blocking the mitochon-
drial long-chain 3ketoacylCoA thiolase, an impor-
tant enzyme for the oxidation of fatty acids. 54,55 In
healthy myocytes, fatty acids are the main substrate
for ATP production by the mitochondria, contributing
6090% of the energy produced; glycolysis and lactate
transformation contribute the remaining 1040%.56
In ischaemic myocytes, where oxygen availability is
limited, the oxidation of glucose requires 1015%
less oxygen than the oxidation of fatty acid to gen-
erate the same amount of ATP (Figure3). By inhibit-
ing the oxidation of fatty acid, trimetazidine might
enhance the energy efficiency of ischaemic myocytes.
The inhibition of fatty-acid oxidation in ischaemic
myocytes also has the potential to prevent lactate and
proton accumulation, both associated with impaired
contractionrelaxationcoupling.
In the randomized TRIMPOLII trial, 57 involving
426 patients with stable angina despite taking metopro-
lol 50mg twice daily, trimetazidine (20mg three times
daily over 12weeks) significantly improved time to
ST-segment depression compared with placebo (+86s
versus +24s; P<0.01) and weekly angina frequency, with
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Comments
Remains controversial despite data from the TACT trial.71
No efficacy on angina perse, but frequently administered
to patients with advanced CAD unsuitable for
revascularization.5
Historical interest. Administered in some areas of Europe
to treat patients with refractory angina.166
Inadequately investigated in patients with ischaemic heart
disease.
no safety concerns. In a small randomized trial of 10
patients with type2 diabetes and persistent angina despite
taking two antianginal drugs, trimetazidine reduced
weekly angina frequency (1.50.8 versus 0.40.7;
P<0.01) and sublingual nitrate doses (1.40.7mg versus
0.10.3mg, P0.001), compared with placebo.58 The
improvement in time to STsegment depression was sub-
stantial (229126s at baseline versus 348145s with tri-
metazidine; P<0.001). However, in a meta-analysis of 23
randomized trials (n=1,378 patients), trimetazidine was
no better than other antianginal drugs in improving time
to STsegment depression or weekly angina frequency,
and no clear reduction in mortality or cardiovascu-
lar events was evident.59 Therefore, despite some evi
dence to suggest a beneficial effect, further clinical trials
are needed.
Perhexiline
Perhexiline enhances mitochondrial glucose oxida-
tion by inhibiting carnitine Opalmitoyltransferase1
and 2, the enzymes responsible for the transfer of
free fatty acids from the cytosol to the mitochondria
(Figure3).60 Early trials suggested clinical improvement
with perhexiline in patients with angina.61 Subsequently,
perhexiline has been shown to improve exercise toler-
ance in patients with cardiomyopathy.62,63 Perhexiline is
used for refractory angina in Australia and New Zealand.
However, the use of perhexiline has been limited because
of phospholipidosis-mediated peripheral neuropathy
andhepatotoxicity.62
lArginine
Coronary endothelial dysfunction contributes to angina
symptoms, and maintaining normal arterial vasomotor
tone is an important target of antianginal therapy.
lArginine theoretically improves coronary blood flow
via nitric-oxide-mediated, endothelium-dependent
vasodilatation.64 In a small study, 26 patients with chest
pain without substantial CAD were randomly allocated
to larginine (3g three times per day) or placebo. 65
lArginine was associated with a marked increase in
REVIEWS

1 Nicorandil K+
Sarcolemma KATP channel Cardiomyocyte

NO Mitochondrion
K+
KATP channel Sarcoplasmic reticulum
cGMP mPTP
K+ Ca2+
pH
PKG PKC
ROS Ca2+ Ca2+

on in ATP
ctr ha
O2 Ele or t c RyR2 SERCA2a Ca2+
nsp LC 3-KAT
tra Ca2+ Ca2+ Ca2+
Fatty acid overload
NADH -oxidation NCX
3Na+
5 4 Trimetazidine
Allopurinol XOR Acetyl-CoA Na+
CPT1/2 INa channel
Krebs Na+ Na+
cycle Pyruvate Na+
NO O2 3 Perhexiline Na+ +
Na
2
Ranolazine
Lactate Pyruvate

Peroxynitrite and Glycolysis

NO availability
Glucose Free fatty Triglycerides
acids Myofilaments

GLUT Fatty acid transporter

Glucose Free fatty

Coronary vasodilatation acids Substrate repletion Excitationcontraction
coupling normalized
ATP
O2
Glucose
Lactate

Figure 3 | Metabolic factors influencing angina. (1) In vascular smooth muscle cells, nicorandil opens membranous K ATP
channels, which induces hyperpolarization by allowing K+ ions to exit the cell. This hyperpolarization in turn limits Ca2+ influx
from outside the cell as well as Ca2+ release from the sarcoplasmic reticulum, resulting into a net drop in intracellular free
Ca2+. This effect of nicorandil is thought mostly to produce vasodilatation of small-resistance coronary vessels. Nicorandil
is also thought to induce vasodilatation of larger coronary arteries and veins through the release of NO free radicals.
Beyond its antianginal property, nicorandil also exerts a disease-modifying effect by mimicking ischaemic preconditioning.
Nicorandil opens mitochondrial KATP channels, which leads to hyperpolarization of the mitochondrion and production of a
sublethal concentration of ROS. The ROS cause the mPTP to close and, therefore, keep the mitochondrion in a constant
state of preparedness in case of actual threatening ischaemic injuries. (2) The influx of Na + into myocytes is exaggerated
during myocardial ischaemia. By inhibiting INa channels, ranolazine prevents the accumulation of Na+ ions, which otherwise
prompts a net influx of Ca2+ by activating the NCX, and leads to Ca2+ overload and uncoupling of excitation and contraction.
Whether ranolazine affects the oxidation of lipids remains controversial. (3) Perhexiline enhances mitochondrial glucose
oxidation by inhibiting CPT1 and CPT2, the enzymes responsible for the transfer of free fatty acids from the cytosol into the
mitochondria. (4) Trimetazidine is thought to block mitochondrial LC3KAT, an important enzyme for the oxidation of fatty
acids. (5) Allopurinol reduces oxidative stress, which increases the availability of oxygen to transform fatty acids and
pyruvate into ATP. Abbreviations: CPT, carnitine Opalmitoyltransferase; GLUT, glucose transporter; K ATP, ATP-sensitive
potassium channel; INa, late sodium current; LC3KAT, mitochondrial long-chain 3ketoacylCoA thiolase; LTCC, voltage-gated
Ltype calcium channel; mPTP, mitochondrial permeability transition pore; NCX, sodium/calcium exchanger; NO, nitric oxide;
PKC, protein kinaseC; PKG, cGMP-dependent protein kinase; ROS, reactive oxygen species; RyR2, ryanodine receptor2;
SERCA2a, sarcoplasmic/endoplasmic reticulum calcium ATPase2a; XO, xanthine oxidase.

coronary blood flow and a significant decrease in plasma Other agents

endothelin in response to acetylcholine.65 In another
small study, 22 patients treated with larginine (6g per
day for 3days) showed improvement in exercise capa
city (530195s to 700173s with larginine versus
501101s to 555106s with placebo; P<0.0002).66 Daily
use of 69g of larginine might be effective in selected
patients with refractory angina, because the drug does
not seem to have adverse effects and is available as an
over-the-counter nutritional product.
The intermittent use of thrombolytic agents (urokinase)
has been reported to improve angina and exercise
capacity in a trial without placebo controls.67 The therapy
seems to be safe,67 but the results need to be tested in a
welldesigned, placebo-controlled trial.
Testosterone might promote endothelium-dependent
relaxation in coronary arteries. In small clinical trials,
supplemental testosterone has improved time to onset
of exercise-induced ST-segment depression, compared

84 | FEBRUARY 2014 | VOLUME 11  www.nature.com/nrcardio

2014 Macmillan Publishers Limited. All rights reserved

with placebo.6870 However, the safety and efficacy of
testosterone supplementation in patients with advanced
CAD is untested.
Opioids have been used for pain control in patients
with angina. However, adverse effects and the poten-
tial for addiction make them an inappropriate choice of
therapy for long-term use.7
Chelation therapy combines disodium ethylene
diaminetetraacetic acid (EDTA) with A and Bvitamins,
electrolytes, and heparin, and is often co-administered
with oral vitamins and minerals. Data from the TACT
trial71 suggested modest efficacy of intravenous disodium
EDTA compared with placebo for improving cardio
vascular outcomes in stable patients with a history of
MI. The effect of chelation therapy was most prominent
in the subgroups of patients with anterior MI (HR0.63,
95%CI 0.470.86) or diabetes (HR0.61, 95%CI 0.45
0.83), in which the lowest hazard ratios for the primary
composite end point of all-cause mortality, recurrent MI,
stroke, coronary revascularization, or hospitalization for
angina were observed.71 However, the efficacy of chelation
therapy to relieve angina remains controversial.72
Noninvasive therapies
Enhanced external counterpulsation
Enhanced external counterpulsation (EECP) is a non
invasive therapy approved for the treatment of refractory
angina that utilizes three sets of pneumatic cuffs around
the lower extremities, which inflate during diastoleto
augment coronary blood flow and deflate in systole
todecrease afterload and increase venous return. 73,74
The mechanism of benefit is likely to be multifactorial,
including recruitment of myocardial collaterals through
activation of growth factors, improvement of endo
thelial function, the release of proangiogenic cytokines,
and a peripheral training effect.7577 Evidence suggests an
increase in the level of nitric oxide, a decrease in the level
of endothelin, and an increase in the level of circulating
CD34+ stem cells after EECP therapy.78,79 These changes
lead to improvements in blood pressure, which might
have a role in the clinical improvement.80
The main randomized trial leading to approval of
the technique was MUSTEECP,81 which involved 139
patients with advanced CAD and refractory angina, and in
which 35h of active counterpulsation was compared with
inactive counterpulsation. No difference was observed in
total exercise duration between the two groups, but time
to exercise-induced STdepression increased signifi-
cantly (P=0.01) and angina was less frequent (P<0.05)
in patients receiving active counterpulsation. 81 EECP
is contraindicated in patients with decompensated HF,
severe peripheral artery disease (including abdominal
aortic aneurysm), or severe aortic insufficiency.73,74 EECP
(35 1h sessions over 7weeks) is approved and reimbursed
in the USA and parts of Europe for the management of
CCS classIII and IV refractory angina.
Extracorporeal shockwave therapy
In low-energy extracorporeal shockwave therapy
(ESWT), a generator system focused with echographic
NATURE REVIEWS | CARDIOLOGY VOLUME 11 | FEBRUARY 2014 | 85
2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
guidance is used to deliver brief, high-amplitude acous-
tic pressure pulses to exert a focal mechanical stress. At
the tissue level, naturally occurring microbubbles inside
and outside of cells oscillate and collapse in response to
the acoustic field. Together, the stress wave and the cavi-
tation effect induce local shear stress, which promotes
insitu expression of chemoattractants, such as stromal
cell-derived factor1, vascular endothelial growth factor
(VEGF), and nitric oxide.8284
ESWT has been compared with placebo in a single-
blind or double-blind fashion in at least six small, ran
domized trials with a total of 240 patients. Improvement
in symptoms, quality of life, and ischaemic thresholds
have been reported. In the largest trial, Wang and col-
leagues compared the effect of an accelerated ESWT
protocol (nine treatment sessions within 1month) or
a standard ESWT protocol (nine treatment sessions
within 3months) with placebo in 55 patients with myo-
cardial ischaemia unsuitable for revascularization.85 The
mean 6min walking test distance at 12months was sig-
nificantly improved in both ESWT-treated groups, but
not in the placebo group (329134m to 452117m
versus 344106m to 478105m versus 364151mto
348132m with the accelerated protocol, standard pro-
tocol, and placebo, respectively; P=0.02).85 The CCS
angina and Seattle Angina Questionnaire scores also
improved in both ESWT groups compared with the
placebo group.85 ESWT has also been combined with
intracoronary bone-marrow-derived mononuclear cell
therapy in 103 patients with chronic postinfarction HF.86
ESWT preconditioning followed by the intracoronary
delivery of bone-marrow-derived mononuclear cells
modestly improved left ventricular ejection fraction at
4months compared with ESWT alone (+3.2% versus
+1.0%; P=0.02), and was associated with improved
functional class and clinical outcomes.86
Shockwaves exert a differential effect on resilient and
calcified tissues and have been associated with minimal
damage to skin and internal organs, even when used at
high-energy levels (for example lithotripsy for kidney
stones)cardiac ESWT typically uses one-tenth of the
energy dose required for lithotripsy. Electrocardiogram
gating on Rwaves avoids impulses during myocardial
repolarization, which could theoretically trigger malig-
nant ventricular arrhythmias. ESWT is a noninvasive
modality that seems to be safe and warrants further study
to determine the optimal dose and protocol as well as its
efficacy in patients with refractory angina.
Invasive therapies
Recanalization of chronic total occlusion
Chronic total occlusions (CTOs) are now success-
fully recanalized in up to 90% of appropriately selected
patients.87 Investigators in observational studies have
reported improvements in long-term outcomes,88 but
few have reported the effect on angina.8991 PCI has not
been directly compared with medical therapy for CTO,92
although two large trials, the DECISIONCTO (n=1,300)
and EUROCTO (n=1,200) trials, were initiated in
2010and 2013, respectively, to address this issue.
REVIEWS
In a meta-analysis of nonrandomized studies per-
formed before the era of drug-eluting stents, outcomes
after successful or failed CTO PCI were compared. 93
Successful recanalization (n=1,581) was associated
with a reduction in residual or recurrent angina at
1236months (OR0.45, 95%CI 0.300.67), 93 and
Olivari and colleagues reported that patients with a suc-
cessfully recanalized CTO were more likely than those
with a failed CTO PCI to have a normal exercise tread-
mill time at 12months (73% versus 47%; P<0.001).91
In 302 consecutive patients who underwent CTO PCI,
those with successful recanalization (n=237) experi-
enced less limitation in physical activity, fewer anginal
episodes, and improved treatment satisfaction than those
with failed PCI (Figure4).94
By contrast, similar proportions of patients with suc-
cessful or failed CTO recanalization self-reported angina
(20% versus 24%; P=0.50) and good-to-excellent quality
of life (73% versus 68%; P=0.52) at 6months after the
procedure.90 In the FACTOR trial,89 a successful CTO PCI
was independently associated with improvement in symp-
toms, function, and quality of life in symptomatic patients,
but the small sample size (n=125), underutilization of
antianginal medication in patients with failed PCI, and
number of patients excluded from the analyses (n=23)
complicate the interpretation of the results.
CTO PCI is not without complications, including
MI, perforation, and death, and can lead to micro-
vascular plugging and distal bed embolization. 95 PCI
itself has no effect on outcomes in patients with stable
CAD, with limited improvement in angina, 96,97 which
raises questions about the large effect size reported
with successful CTO PCI.98 Current practice guidelines
recommend CTO PCI for patients who are unsuit-
able for CABG surgery, remain symptomatic despite
optimal medical therapy, and have a documented large
ischaemicburden.99,100
Reduction of the coronary sinus
Percutaneous reduction of the coronary sinus is a con-
temporary adaptation of a principle originally described
by Beck and Leighninger, who performed surgical nar-
rowing of the coronary sinus to restrict drainage of
efferent venous blood from the left circulation.101 The
theory was based on blood-flow redistribution to ischae-
mic myocardium via a trans-sinusal pressure gradient,
creating an imbalance in regional capillary pressure and
allowing for redistribution of coronary arterial blood to
underperfused myocardium. Under physiological con
ditions, the subepicardial arteries constrict in response
to stress, and redirect blood into the subendocardiuma
compensatory mechanism that might be dysfunctional
in patients with both advanced CAD102 and HF.103 The
Neovasc Reducer(Neovasc, Inc., Canada) is a stainless
steel, balloon-expandable, hourglass-shaped device that
creates a controlled narrowing of the coronary sinus. The
device was associated with an improvement in ischae-
mia in a single-arm, phaseI trial involving patients with
refractory angina, and is currently being studied in the
phaseII COSIRA trial.104,105
86 | FEBRUARY 2014 | VOLUME 11  www.nature.com/nrcardio
2014 Macmillan Publishers Limited. All rights reserved
100
P <0.05
80
Successful
Failed
Population (%)
60
40
20
0
Once per day Once per week <Once per week
Angina frequency
Figure 4 | Successful percutaneous coronary intervention
for chronic total occlusion is associated with reduced
angina frequency. The majority (87%) of patients who were
successfully recanalized experienced angina symptoms
less than once per week, compared with 56.5% of patients
with failed recanalization. Reprinted from Int. J. Cardiol.
161(1) Borgia, F. etal. Improved cardiac survival, freedom
from MACE and angina-related quality of life after
successful percutaneous recanalization of coronary artery
chronic total occlusions. 3138 2012, with permission
from Elsevier.
Therapeutic angiogenesis
The use of protein growth factors, gene therapy, or
stem-cell therapy to enhance the natural process of
angiogenesis has been termed therapeutic angiogenesis.
These techniques are supported by successful preclinical
studies in the setting of ischaemic myocardium.106108
Protein and gene therapy
Two large, randomized, placebo-controlled trials involv-
ing intracoronary VEGF and fibroblast growth factor
(FGF) showed no efficacy in terms of the primary end
point (exercise time), but positively affected the second-
ary end points (angina and quality of life) in patients
with angina.16,17 A short half-life was thought to be the
major limitation for the angiogenic proteins, which lead
to an interest in gene therapy in an attempt to prolong
the angiogenic stimulus. Intracoronary delivery of an
adenovirus encoding FGF5 (Ad5FGF) was successful
in the AGENT 109 and AGENT2110 trials, which lead
to two large, phaseIII trials. AGENT3 and AGENT4
were double-blind trials using two different dose groups
(low dose of Ad5FGF4: 1109 viral particles, high dose
of Ad5FGF4: 11010 viral particles) and placebo in
a 1:1:1 randomization ratio with a primary end point
of change in exercise treadmill time from baseline to
12weeks. A pooled analysis of AGENT3 and AGENT4
showed no difference in the primary end point, but did
show a significant reduction in angina and a substantial
exercise benefit in high-risk patients, defined as those
aged >55years, angina classIIIIV, and baseline exer-
cise time <300s.18 In two moderately sized (n=80 and
n=93), randomized, placebo-controlled trials, no effect
of intramyocardial delivery of the gene encoding VEGF
 REVIEWS

a BMSC Control
Study or subgroup Events Total Events Total Weight RR (95% CI) RR (95% CI)

Losordo (2007) 0 18 0 24 Not estimable

Losordo (2011) HD 0 56 2 27 12.1% 0.10 (0.001.98)

Losordo(2011) LD 0 55 1 28 7.1% 0.17 (0.014.11)

Perin (2011) 0 20 0 10 Not estimable

Perin (2012a) 1 61 0 31 2.4% 1.55 (0.0636.94)

Perin (2012b) 0 10 0 10 Not estimable

Pokushalov (2010) 6 55 21 54 76.6% 0.28 (0.120.64)

Tse (2007) 0 19 0 9 Not estimable

van Ramshort (2009) 1 25 0 25 1.8% 3.00 (0.1370.30)

Wang (2010) 0 56 0 56 Not estimable

Total (95% CI) 8 375 24 274 100.0% 0.33 (0.170.65)

0.01 0.1 1 10 100

Favours BMSC Favours control
b BMSC Control Mean difference Mean difference
Study or subgroup Mean SD Total Mean SD Total Weight (95% CI) (95% CI)

Losordo (2007) 8.6 10.3 18 16.0 19.3 6 1.7% 7.40 (23.56 to 8.76)

Losordo (2011) HD 7.2 8.0 53 11.0 8.5 50 44.8% 3.80 (6.99 to 0.61)

Losordo (2011) LD 6.3 8.7 53 11.0 8.5 50 41.4% 4.70 (8.02 to 1.38)

Pokushalov (2010) 4.2 8.4 49 19.6 29.4 33 4.3% 15.40 (25.70 to 5.10)

Wang (2010) 5.6 15.7 56 15.5 24.7 56 7.8% 9.90 (17.57 to 2.23)

Total (95% CI) 229 195 100.0% 5.21 (7.35 to 3.07)

20 10 0 10 20
Favours BMSC Favours control
Figure 5 | Effect of BMSCs on primary outcomes in patients with refractory angina. a | Mortality. b | Mean change in angina
frequency (number of episodes per week) at the end of the study. Abbreviations: BMSC, bone-marrow stem cell; HD, high
dose; LD, low dose; RR, relative risk. Reprinted from Fisher, S.A. etal. PLoS ONE 8, e64669 (2013), which is published
under an openaccess licence by BioMed Central.

on the primary end points (ischaemia assessed by single-
photon emission computed tomography) was reported,
although an improvement was noted in the secondary
end point (angina).19,111 Despite an excellent safety record
and trends towards positive outcomes, more-effective
angiogenic agents were clearly needed, which stimulated
interest in stem cells.
Cell therapy
Experimental evidence suggests that cell therapy can
promote neovascularization and consequently improve
myocardial perfusion and contractile function.112 Beyond
differentiation or regeneration, cell therapy is thought
to exert paracrine effects via a vast array of proangio-
genic factors that act locally to alter myocardial func-
tion, reduce apoptosis, and recruit both resident and
circulating stemcells.112
A systematic review and meta-analysis was performed
of nine randomized trials in which autologous bone-
marrow-derived mononuclear cell therapy (including
trials with CD34+ cells) was used in patients with either
ischaemic HF or refractory angina and no revascular
ization option (n=363 cell-treated versus 296 placebo).
The results indicated that cell therapy might reduce
mortality over 612months (relative risk0.33, 95%CI
0.170.65, P=0.001), and reduce angina symptoms as
assessed by CCS angina classification (mean differ-
ence0.55, 95%CI 1.00 to 0.10, P=0.02) and the
weekly angina count (mean difference5.21 angina epi-
sodes, 95%CI 7.35 to 3.07, P<0.00001; Figure5).113 The
results of this m
eta-analysis have been validated by two
othergroups.114,115
In particular, CD34+ cells seem to be promising in
patients with refractory angina. Wang and colleagues com-
pared the intracoronary transplantation of bone-marrow
CD34+ cells (mean 5.6107 cells), with placebo in 112
patients with refractory angina. At 6months, the weekly
angina frequency was significantly improved in patients
treated with CD34+ cells (15.64.0) compared with
placebo (3.01.2; P<0.01).116 In the largest trial, Losordo
and colleagues compared one of two doses of CD34+ cells
(1105 or 5105 cells per kg) to a placebo in 167 patients
with classIIIIV refractory angina whowere not suit-
able for revascularization.117 CD34+ cells weremobilized
with granulocyte colony-stimulating factor, collected by
leukopheresis, and injected directly into the ischaemic
myocardium using electromechanical (NOGA, Cordis
Corporation, USA) guidance.117 At6months, the weekly

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2014 Macmillan Publishers Limited. All rights reserved
REVIEWS

Figure 6 | The neurogenic components of angina. The cardiac pain signal can be modulated anywhere in the transmission

pathway from the cardiac tissue to the brain. a | Tissue-level modulation of afferent signal. Ischaemia leads to increased
concentrations at the tissue level of adenosine, bradykinin, and substanceP, which stimulate the chemosensitive
andmechanosensitive nerve endings of the myocardium enroute to the spinal track via the afferent myelinated (A) and
unmyelinated (C) fibres. b | Spinal-level modulation of afferent signal. SCS is thought to activate the Afibres (1), which
synapse onto the dorsal horn with the GABAergic or cholinergic interneurons (2). These interneurons are thought to release
neurotransmitters (such as GABA), which reduce the excitability of neurons projecting to the STT (3). The net consequence
isthat subsequent nociceptive input carried by the A and Cfibres is downmodulated (4). Likewise, stimulation of the
Afibres is also thought to inhibit the sympathetic efferent fibres responsible for the vasoconstriction of coronary arteries
(mechanism not illustrated). c | Subcutaneous-level modulation of afferent signal. SENS targets subcutaneous nerve
endings located in the precordial regions from where angina radiates. Electrodes are positioned subcutaneously on each
side of the sternum. d | Central-level modulation of afferent signals. Classic angina occurs in response to stress, either
physical or emotional, and is also affected by comorbidities and context. This panel illustrates the importance of a holistic
approach, including psychological health, to manage patients with persistent cardiac pain successfully. Self-management
training and citalopram are interventions known positively to affect mental stress-induced myocardial ischaemia, and are an
important aspect of patient-centred care. Abbreviations: CNS, central nervous system; GABA, aminobutyric acid; SCS,
spinal-cord stimulation; SENS, subcutaneous electrical nerve stimulation; STT, spinothalamic track. Panels a and d reprinted
from Can. J. Cardiol. 2(Suppl.) Rosen, SD. From heart to brain: the genesis and processing of cardiac pain. S7S19 2012,
with permission from Elsevier. Panel b reprinted from Prager, J.P. What does the mechanism of spinal cord stimulation tell us
about complex regional pain syndrome? Pain Med. 11(8), 12781283 (2013), with permission from Wiley.

angina frequency was significantly lower in the low-dose
group than in placebo-treated group (6.81.1 versus
10.91.2; P=0.02), with a significant improvement in
exercise time (139115s versus 69122s; P=0.014).117
These results were sustained at 12months.117 The results
in the high-dose group were similar to those in the low-
dose group, with no evidence of a doseresponse rela-
tionship.117 Alarge, phaseIII trial is ongoing, which will
potentially lead to regulatory approval of CD34+ cells in
patients with refractory angina.118 Potential future direc-
tions for cell therapy include delivery via retroperfusion
in the coronary sinus,119 and gene-modification of cells to
enhance their cytoprotective and proangiogenic proper-
ties,120 as well as allogeneic cells, cardiac-derived cells, or
pluripotentcells.121
Neuromodulation
Neuromodulation is the use of chemical, mechanical, or
electrical means to interrupt a pain signal anywhere in the
transmission pathway from the periphery to the brain.
In addition to pain relief, neuromodulation of thedis-
eased heart has the potential to alter the unfavourable
sympathetic afference responsible for vasoconstriction,
which leads to ischaemia. In particular, neuromodulation
seems to be useful for patients with a prominent neuro-
genic, rather than ischaemic, component to their cardiac
pain(Figure6).
Spinal-cord modulation
Transcutaneous electrical nerve stimulation is a non-
invasive option reported to be successful in relieving
angina. This technique is often used temporarily to
assess responsiveness to neuromodulation before a
moredefinitive measure, such as SCS, is initiated.122
SCS has been used for 3decades in a variety of chronic
pain syndromes. For cardiac pain, a multipolar electrode
is surgically positioned in the epidural space between the
C7 and T4 vertebrae, near to the dorsal column where
the myocardial afferent sympathetic fibres synapse with
second-order sensory neurons in the dorsal horns. SCS
is thought to alter the dorsal-horn neurochemistry by
promoting the release of aminobutyric acid, which
antagonizes the effect of the descending inhibitory path-
ways that are known to favour the transmission of the
nociceptive afference.123 SCS might have a dual effect
on angina. In addition to the analgesic effect described
above, SCS has been hypothesized to mediate a sympa-
thicolytic effect, which could indirectly reduce vasocon-
striction and myocardial ischaemia.124,125 The association
between SCS, the autonomous nervous system, and
reduction in ischaemia has, however, beeninconsistent.126
During SCS, the electrode is linked to a programmable
pulse generator with settings customized for each patient.
The therapy is self-administered and typically requires
stimulation for 1h, three times per day, and whenever
angina occurs. SCS has been compared with various
control treatments (such as CABG surgery and percuta-
neous myocardial laser revascularization) in seven ran-
domized trials. A meta-analysis of these trials showed
a significant improvement for patients allocated to SCS
in terms of exercise capacity (standardized mean differ-
ence [SMD]0.76, 95%CI 0.071.46, P=0.03; Figure7),
and health-related quality of life (SMD0.83, 95%CI
0.321.34, P=0.001). 127 The ESC Joint Study Group
on the Treatment of Refractory Angina granted SCS a
classIa recommendation >1decade ago.3 Subsequently,
the authors of the 2012CCS guidelines for the manage-
ment of patients with refractory angina gave a weak
recommendation for the use of SCS to improve exercise
capacity and quality of life, owing to methodological
concerns about the available evidence.4 In registry data,
which tend to reflect real-world practice, SCS has been
associated with reductions in both angina frequency and
nitrate consumption.128 Two small, single-blind trials
suggested a benefit of SCS,129,130 but investigators in the
largest blinded trial attempted to date, STARTSTIM,131
had difficulty reaching enrolment targets and showed no
difference between active-treatment and control groups,
both of which showed improvement consistent with a
placebo effect. Despite two positive systematic reviews
and the ESC recommendation, SCS is not approved in
the USA.127,132

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 REVIEWS

d
Neurochemistry and structure
Opioids
Dopamine
GABA
Mood Catecholamines Comorbidity
Depression Maladaptive plasticity Other visceral
Context Anxiety Neurodegeneration pain Cognitive set
Pain beliefs Anger Hypertension Hypervigilance
Expectation Hostility Diabetes mellitus Attention
Placebo CNS Distraction

Escitalopram

Pain Mental stress-induced

signal myocardial ischaemia Self-management
training

b A-fibres Sympathetic
1 chain
SCS
STT
A-fibres
and C-fibres
2 Temporary
4 sympathectomy

(stellate ganglion
33 blockade)

a Afferent neural traffic

Abnormal Abnormal
c stretch stretch

Myocardial A
+ and C fibres +
+
Neurokinin-1 A2 receptor BK receptor
receptor

Substance P Adenosine Bradykinin

Transient products Lactic acid

of lipid oxidation H+
K+

Probe

Spinal-cord
stimulation SENS pulse
generator

Subcutaneous electrical nerve stimulation
Subcutaneous electrical nerve stimulation (SENS) is a
fairly new method to treat refractory angina, although
the technique has been used to treat other chronic pain
disorders.133 SENS targets subcutaneous nerve endings
located in the precordial regions, from where the angina
radiates. Multipolar electrodes are subcutaneously
implanted in the parasternal area, where patients typi-
cally feel anginal pain, and tunnelled to a pulse genera-
tor located in the upper abdomen. In a pilot study of
seven patients, Buiten and colleagues demonstrated the
safety and feasibility of the concept using a stimulation
protocol of three periods of 1h daily.133 All patients
experienced reductions in the frequency of angina
and sublingual nitrate consumption.133 As with SCS,
potential interactions between the pulse generator and
implantable defibrillators is of concern and warrants
additional safety information. If effective, SENS might
prove useful for patients who require dual antiplatelet
therapy or anticoagulation, in whom positioning an
electrode in the epidural space is associated with a high
risk of bleeding.

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2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
SCS Control
Study or subgroup Mean SD Total Mean SD
Jessurun (1999) 14.6 3.2 12 15.3 3.4
Hauvast (1998) 19 14 13 0.2 17
Eddicts (2007) 394 55 12 337 55
DeJongste (1994) 827 138 8 694 67
Subtotal (95% CI) 45
Figure 7 | Effect of SCS on exercise capacity. Results from a meta-analysis of clinical trials, showing that SCS improves
exercise capacity in patients with refractory angina. Abbreviation: SCS, spinal-cord stimulation. Reprinted from Taylor, R.S.
etal. BMS Cardiovasc. Disord. 9, 13 (2009), which is published under an open-access licence by BioMed Central.
Cardiac sympathectomy
The left stellate (cervicothoracic) ganglion is a readily
accessible point of convergence for sympathetic fibres
that transmit the afferent cardiac pain signal to the
intermediolateral grey column in the thoracic spinal
cord enroute to the central nervous system. Temporary
sympathectomy by stellate ganglion blockade has
been associated with anecdotal success in patients
withangina, but has never formally been assessed in an
appropriately designed trial. Alternative routes for tem-
porary (high thoracic epidural analgesia) and perma-
nent sympathectomy have also been used with varying
success.134,135 Owing to the lack of appropriate evidence,
no practice recommendations can be formulated about
cardiacsympathectomy.3,4
Transmyocardial laser revascularization
The development of transmyocardial laser revasculariza-
tion (TMLR) was developed according to the theory that
channels in the myocardium would carry blood from the
ventricular cavity directly to the myocardium, similarly
to those in reptilian hearts.2 However, the mechanism
of benefit is more likely to be the result of injury stimu-
lating angiogenesis or denervation. TMLR is performed
epicardially during a surgical procedure (open chest or
robotic) or endocardially via a percutaneous approach
(PTMLR). TMLR, either alone or in conjunction with
CABG surgery, is approved by the FDA for the treatment
of refractory angina.
A series of open-chest surgical trials showed improve-
ments in angina, exercise time, and myocardial perfu-
sion, but lacked placebo controls for obvious reasons.1214
In the PACIFIC trial,15 PTMLR and medical therapy was
compared with medical therapy alone in 221 patients
with CCS classIII angina. PTMLR was associated with
an improvement in exercise tolerance.15 Unfortunately,
the only double-blind, placebo-controlled trial of
PTMLR (DIRECT136), which involved 298 patients (98
placebo; 98 low-dose, 1015 channels; 102 high-dose,
2025 channels), showed no difference in the primary
end point (change in exercise duration) at 6month
follow-up. All three groups had a significant improve-
ment in symptoms, highlighting the importance of the
placebo effect.136 Additionally, the 30day incidence
of MI was higher in the aggregate of patients treated
90 | FEBRUARY 2014 | VOLUME 11  www.nature.com/nrcardio
2014 Macmillan Publishers Limited. All rights reserved
Mean difference Mean difference
Total Weight (95% CI) (95% CI)
12 27.2% 0.20 (1.01 to 0.60)
12 25.7% 1.20 (0.332.06)
12 25.8% 1.00 (0.141.86)
9 21.4% 1.19 (0.132.24)
45 100.0% 0.76 (0.071.46)
4 2 0 2 4
Favours control Favours SCS
with either the low dose or the high dose than in those
who received placebo (nine patients versus no patients;
P=0.03).136 The results of DIRECT136 dampened enthu-
siasm for TMLR, although the two approaches (TMLR
and PTMLR) are not necessarily equivalent. TMLR is
contraindicated in patients with a low left ventricular
ejection fraction or recent MI, because morbidity and
mortality are substantially increased in these patients.4,6,7
Patient-centred care
Specialized clinics for refractory angina
A multidisciplinary approach is often needed for the
optimal treatment of patients with refractory angina. In
addition to physical rehabilitation, physical and occupa-
tional therapy, drug optimization, and aggressive risk-
factor modification, a multidisciplinary team can offer
advanced options customized to a patients profile.20 The
opinions of interventional cardiologists and cardiac sur-
geons are crucial to periodical reviews of the suitability
of patients for revascularization in the context of a risk-
to-benefit ratio modified by a diminished quality of life.5
Anaesthesiologists and neurosurgeons can provide input
into the neuropathic component of refractory angina.
Nurses and psychotherapists will complete the pro-
gramme with self-management training and reassurance
when appropriate. A multidisciplinary approach includ-
ing medical and behavioural interventions and physical
rehabilitation has been associated with improved health-
related quality of life,137 enhanced physical ability,138 and
reduced hospital readmission.139
Mental stress-induced myocardial ischaemia
Classic angina occurs in response to stress, either
physical or emotional. Mental stress-induced myocar-
dial ischaemia (MSIMI) is infrequently diagnosed, but
might actually be more prevalent than exercise stress-
induced myocardial ischaemia.140 In a study involving
participants with stable CAD, MSIMI and exercise-
induced ischaemia occurred in 43% and 34% of the
cohort, respectively (P=0.002).141 Relative to physical
stress, mental stress results in higher heart-rate and
bloodpressure responses.142
Whereas the association between MSIMI and future
adverse cardiovascular events is well documented, 140
the role of pharmacological interventions targeted at
 REVIEWS

reducing MSIMI has not been well studied. In the ran-
domized REMIT trial,143 the effect of 6weeks of selec-
tive serotonin-reuptake inhibitor (SSRI) therapy was
compared with placebo in patients with CAD and docu-
mented MSIMI. More patients taking escitalopram were
freefromMSIMIcompared with those receiving placebo
(34.2% versus 17.5%, respectively; unadjusted odds
ratio2.62),143 but no effect on exercise-induced ischae-
mia was reported. Escitalopram did not affect symptoms
of depression, but did improve anxiety and emotional
reactions to mentalstress.143
SSRIs have been hypothesized to prevent micro
circulatory dysfunction triggered by an inappropri-
ate response to central nervous system stress and the
hypothalamicpituitaryadrenal axis system, but the
exact mechanism of preventing MSIMI remains unclear.
The results of SSRI in patients with CAD or HF have
been mixed, and not formally studied in refractory
angina. 144,145 As with many of the novel drugs, such
as trimetazidine and ranolazine, SSRIs in general and
escitalopram in particular might target ischaemia via
mechanisms that are not modified by conventional
anti-ischaemic drugs. Escitalopram is to be used with
caution if major symptoms of depression are present,
given the increased risk of suicide in particular subsets
of patients.146
Self-management training
The CSC practice guidelines on refractory angina
mention self-management training as an evidence-based
treatment that can be considered to reduce angina symp-
toms and the associated use of nitrates, and to improve
quality of life.4 Little known by physicians, self-manage-
ment training is traditionally advocated by nurses and
psychologists as a series of cognitive-behavioural inter-
ventions and learning materials designed to educate
patients and demystify angina. The overall objectives
are to improve knowledge about the disease, and how
to control angina and its associated symptoms effec-
tively. Self-management training targets daily problems
encountered by patients, such as the anxiety associated
with pain, fatigue, and decreased mobility.147 During
self-management training, patients are taught safe
exercise habits, energy conservation and pacing, and
decision-making skills. McGillion and colleagues system-
atically reviewed the efficacy of self-management train-
ing in 949 patients with angina from seven randomized
trials and reported fewer weekly angina episodes (2.85,
95%CI 4.04 to 1.66) and reduced sublingual nitrate
use (3.69, 95%CI 5.50 to 1.89), as well as improved
angina-related quality of life in patients undergoing
selfmanagement training.148
Conclusions
Patients with advanced CAD and refractory angina are a
complex and growing population. Traditionally thought
to be at high cardiovascular risk, contemporary manage-
ment of these patients with aggressive risk-factor modi-
fication, antianginal medications, and revascularization
has resulted in a substantial improvement in their long-
term survival, which has changed the focus of therapy
onto quality of life. A growing number of novel pharma-
cological, noninvasive, and invasive therapeutic modal
ities are under investigation, with the aim of improving
care for this challenging population of patients.
Review criteria
The authors searched the PubMed, EMBASE, and
CENTRAL databases for full-text papers published
between January1990 and July2013. The following
search terms were used: angina, refractory
angina, cardiac pain, nicorandil, trimetazidine,
perhexiline, molsidomine, Larginine, intermittent
thrombolytics, testosterone, coronary sinus
reduction, EECP, extracorporeal shock wave
therapy, chronic total occlusion, angiogenesis,
gene therapy, neuromodulation, spinal cord
stimulation, transmyocardial laser revascularization,
mental stress-induced myocardial ischemia, self-
management training, allopurinol, ranolazine,
ivabradine, fasudil, hydroxyfasudil, escitalopram,
imipramine, and cell therapy. Practice guidelines
from Canada, Europe, and the UK and were checked for
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Author contributions
All the authors contributed substantially to
researching data for the article, discussing its
content, writing the manuscript, and reviewing/
editingit before submission.
 REVIEWS

CORRECTION
Treatment of refractory angina in patients notsuitable for
revascularization
Timothy D. Henry, Daniel Satran and E. Marc Jolicoeur
Nat. Rev. Cardiol. advance online publication 24 December 2013; doi:10.1038/nrcardio.2013.200
In the version of this article initially published online, the drug citalopram shown in
Figure6d should have been escitalopram. The error has been corrected for the print, HTML,
and PDF versions of the article.

NATURE REVIEWS | CARDIOLOGY VOLUME 11 | FEBRUARY 2014 | i

2014 Macmillan Publishers Limited. All rights reserved