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

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

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

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

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Table 1 | Pharmacological therapies for refractory angina


Pharmacological Proposed mechanism of action Comments
agent
Oxygen-sparers
Allopurinol Inhibits xanthine oxidase and its associated Allopurinol has not been shown to improve symptoms or
oxidative stress, which prevents oxygen toprevent major adverse cardiac events. Despite the wide
wastage,endothelial dysfunction, and availability of the drug, its use at the high doses described
substratedepletion.50,52 in clinical trials should remain investigational until
additional safety data are available.50,51
Late Na+ current inhibitors
Ranolazine Inhibits late inward Na+ current, which prevents Ranolazine exerts a dose-dependent prolongation of the
Ca2+ overload and increased diastolic tension QT interval. The FDA recommends restricting its use to
(which impairs coronary perfusion).39 patients with persistent symptoms despite adequate
Improves regional coronary blood flow in areas doses of evidence-based therapies.
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, Inadequately investigated in patients with ischaemic heart
which transfer free fatty acid from the cytosol disease. Growing clinical experience in patients with
intomitochondria.60 congestive heart failure. Plasma concentration required for
dose titration.
Trimetazidine Reversibly inhibits mitochondrial long-chain Chronic trimetazidine use has been associated with
3ketoacylCoA thiolase, an important enzyme extrapyramidal adverse reactions, including Parkinsonism,
infatty-acid oxidation in mitochondria.55 gait disorders, and restless leg syndrome.149
Vasodilators
lArginine Improves coronary blood flow via nitric-oxide- Inadequately investigated in patients with ischaemic heart
mediated, endothelium-dependent vasodilatation.64 disease.
Fasudil and Inhibit Rho kinase, which possibly reduces Have shown anti-ischaemic, but no antianginal, effects
hydroxyfasudil calcium sensitization of vascular smooth inpatients with151 or without150 concomitant antianginal
muscle150 to maintain coronary vasodilatation medication. Currently available in Japan for prevention
andprevent vasospasm.151 ofcentral nervous system vasospasm associated with
subarachnoid haemorrhage. Potentially useful for
vasospastic angina.
Molsidomine Direct nitric oxide donor (sydnonimine), which In a double-blind, randomized, controlled trial (n=533),
vasodilates the coronary vasculature. 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
Nicorandil Nitrate-like effect that vasodilates the coronary Acceptable substitute for long-acting nitrates when nitrate
vasculature and venous system tolerance is a concern; not associated with impaired
Cardioprotective effects, presumably through endothelial function during chronic use.30 Nicorandil has
opening of mitochondrial ATP-sensitive been associated with anal ulceration.155
potassiumchannels.154
If channel blockers
Ivabradine If channels blockers reduce the automaticity of In patients with ischaemic cardiomyopathy and congestive
spontaneous depolarization in the sinoatrial node heart failure, ivabradine was associated with a 24%
cells, with resultant bradycardia.156 reduction in the occurrence of cardiovascular death and
Possible vasodilatory effect when used instead hospitalization for myocardial infarction or heart failure.35
ofblockers.33,157 In 15% of patients, ivabradine was associated with
headache, dizziness, and brightness in the visual field.
Antidepressants
Escitalopram SSRIs targeted at reducing the effect of mental Escitalopram exerts its anti-ischaemic effects independently
stress-induced haemodynamic response,143 such as of any effects it might have on symptoms of depression.143
coronary artery vasoconstriction and microvascular The effect of escitalopram on angina symptoms remains
changes, along with metabolic risk factors.158 unknown. MSIMI is typically without pain and occurs with
SSIRs are inhibitors of the 5hydroxytryptamine lower levels of oxygen demand than exercise-induced
platelet receptor, which reduces platelet ischaemia. Escitalopram is associated with an increased
aggregation.159 risk of suicide in particular subsets of patients.
Imipramine Tricyclic antidepressant thought to exert an Historical interest. Investigated in patients with cardiac
analgesic effect on the visceral component pain and a normal coronary angiogram, and was shown to
associated with cardiac pain. improve symptoms,160 but not quality of life.161
Inadequately studied in patients with advanced CAD and
refractory angina.

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Table 1 (Cont.) | Pharmacological therapies for refractory angina


Pharmacological Proposed mechanism of action Comments
agent
Chelation therapy
EDTA (associated Mechanism of action uncertain, possibly Remains controversial despite data from the TACT trial.71
with various associated with reduced oxidation of low-density No efficacy on angina perse, but frequently administered
vitamins) lipoprotein,162 vasodilatory effects,163 and to patients with advanced CAD unsuitable for
enhanced production of tissue plasminogen revascularization.5
activator.149
Rheological agents
Intermittent Depletion of plasma fibrinogen, which reduces Historical interest. Administered in some areas of Europe
thrombolytics blood viscosity and improves the rheological to treat patients with refractory angina.166
(urokinase) properties of blood in the microcirculation.67,164,165
Testosterone
Testosterone Promotes endothelium-dependent relaxation of Inadequately investigated in patients with ischaemic heart
coronary arteries. disease.
Abbreviations: CAD, coronary artery disease; EDTA, ethylenediaminetetraacetic acid; MSIMI, mental stress-induced myocardial ischaemia; SSRI, selective
serotonin-reuptake inhibitor.

Allopurinol no safety concerns. In a small randomized trial of 10


Allopurinol, a well-accepted therapy for gout, reduces oxi- patients with type2 diabetes and persistent angina despite
dative stress mediated by xanthine oxidase (Figure3).49,50 taking two antianginal drugs, trimetazidine reduced
By inhibiting oxidative stress, allopurinol increases the weekly angina frequency (1.50.8 versus 0.40.7;
level of oxygen available to transform fatty acids and P<0.01) and sublingual nitrate doses (1.40.7mg versus
pyruvate into energy. Allopurinol has also been shown 0.10.3mg, P0.001), compared with placebo.58 The
to mediate an improvement in endothelium-dependent improvement in time to STsegment depression was sub-
vasodilatation in patients with CAD 51 or HF. 52 In a stantial (229126s at baseline versus 348145s with tri-
small trial involving 65 patients with stable angina (87% metazidine; P<0.001). However, in a meta-analysis of 23
taking blockers), allopurinol 300mg twice daily was randomized trials (n=1,378 patients), trimetazidine was
superior to placebo in prolonging time to both chest pain no better than other antianginal drugs in improving time
(+43s,95%CI 3158s) and STsegment depression (+58s, to STsegment depression or weekly angina frequency,
95%CI 4577s), but the trial was not powered to detect and no clear reduction in mortality or cardiovascu-
a difference in angina burden, quality of life, or clinical lar events was evident.59 Therefore, despite some evi
outcomes.53 Larger trials are needed to test this benefit. dence to suggest a beneficial effect, further clinical trials
are needed.
Trimetazidine
Trimetazidine is a metabolic agent that increases Perhexiline
glucose oxidation, possibly by blocking the mitochon- Perhexiline enhances mitochondrial glucose oxida-
drial long-chain 3ketoacylCoA thiolase, an impor- tion by inhibiting carnitine Opalmitoyltransferase1
tant enzyme for the oxidation of fatty acids. 54,55 In and 2, the enzymes responsible for the transfer of
healthy myocytes, fatty acids are the main substrate free fatty acids from the cytosol to the mitochondria
for ATP production by the mitochondria, contributing (Figure3).60 Early trials suggested clinical improvement
6090% of the energy produced; glycolysis and lactate with perhexiline in patients with angina.61 Subsequently,
transformation contribute the remaining 1040%.56 perhexiline has been shown to improve exercise toler-
In ischaemic myocytes, where oxygen availability is ance in patients with cardiomyopathy.62,63 Perhexiline is
limited, the oxidation of glucose requires 1015% used for refractory angina in Australia and New Zealand.
less oxygen than the oxidation of fatty acid to gen- However, the use of perhexiline has been limited because
erate the same amount of ATP (Figure3). By inhibit- of phospholipidosis-mediated peripheral neuropathy
ing the oxidation of fatty acid, trimetazidine might andhepatotoxicity.62
enhance the energy efficiency of ischaemic myocytes.
The inhibition of fatty-acid oxidation in ischaemic lArginine
myocytes also has the potential to prevent lactate and Coronary endothelial dysfunction contributes to angina
proton accumulation, both associated with impaired symptoms, and maintaining normal arterial vasomotor
contractionrelaxationcoupling. tone is an important target of antianginal therapy.
In the randomized TRIMPOLII trial, 57 involving lArginine theoretically improves coronary blood flow
426 patients with stable angina despite taking metopro- via nitric-oxide-mediated, endothelium-dependent
lol 50mg twice daily, trimetazidine (20mg three times vasodilatation.64 In a small study, 26 patients with chest
daily over 12weeks) significantly improved time to pain without substantial CAD were randomly allocated
ST-segment depression compared with placebo (+86s to larginine (3g three times per day) or placebo. 65
versus +24s; P<0.01) and weekly angina frequency, with lArginine was associated with a marked increase in

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

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REVIEWS

with placebo.6870 However, the safety and efficacy of guidance is used to deliver brief, high-amplitude acous-
testosterone supplementation in patients with advanced tic pressure pulses to exert a focal mechanical stress. At
CAD is untested. the tissue level, naturally occurring microbubbles inside
Opioids have been used for pain control in patients and outside of cells oscillate and collapse in response to
with angina. However, adverse effects and the poten- the acoustic field. Together, the stress wave and the cavi-
tial for addiction make them an inappropriate choice of tation effect induce local shear stress, which promotes
therapy for long-term use.7 insitu expression of chemoattractants, such as stromal
Chelation therapy combines disodium ethylene cell-derived factor1, vascular endothelial growth factor
diaminetetraacetic acid (EDTA) with A and Bvitamins, (VEGF), and nitric oxide.8284
electrolytes, and heparin, and is often co-administered ESWT has been compared with placebo in a single-
with oral vitamins and minerals. Data from the TACT blind or double-blind fashion in at least six small, ran
trial71 suggested modest efficacy of intravenous disodium domized trials with a total of 240 patients. Improvement
EDTA compared with placebo for improving cardio in symptoms, quality of life, and ischaemic thresholds
vascular outcomes in stable patients with a history of have been reported. In the largest trial, Wang and col-
MI. The effect of chelation therapy was most prominent leagues compared the effect of an accelerated ESWT
in the subgroups of patients with anterior MI (HR0.63, protocol (nine treatment sessions within 1month) or
95%CI 0.470.86) or diabetes (HR0.61, 95%CI 0.45 a standard ESWT protocol (nine treatment sessions
0.83), in which the lowest hazard ratios for the primary within 3months) with placebo in 55 patients with myo-
composite end point of all-cause mortality, recurrent MI, cardial ischaemia unsuitable for revascularization.85 The
stroke, coronary revascularization, or hospitalization for mean 6min walking test distance at 12months was sig-
angina were observed.71 However, the efficacy of chelation nificantly improved in both ESWT-treated groups, but
therapy to relieve angina remains controversial.72 not in the placebo group (329134m to 452117m
versus 344106m to 478105m versus 364151mto
Noninvasive therapies 348132m with the accelerated protocol, standard pro-
Enhanced external counterpulsation tocol, and placebo, respectively; P=0.02).85 The CCS
Enhanced external counterpulsation (EECP) is a non angina and Seattle Angina Questionnaire scores also
invasive therapy approved for the treatment of refractory improved in both ESWT groups compared with the
angina that utilizes three sets of pneumatic cuffs around placebo group.85 ESWT has also been combined with
the lower extremities, which inflate during diastoleto intracoronary bone-marrow-derived mononuclear cell
augment coronary blood flow and deflate in systole therapy in 103 patients with chronic postinfarction HF.86
todecrease afterload and increase venous return. 73,74 ESWT preconditioning followed by the intracoronary
The mechanism of benefit is likely to be multifactorial, delivery of bone-marrow-derived mononuclear cells
including recruitment of myocardial collaterals through modestly improved left ventricular ejection fraction at
activation of growth factors, improvement of endo 4months compared with ESWT alone (+3.2% versus
thelial function, the release of proangiogenic cytokines, +1.0%; P=0.02), and was associated with improved
and a peripheral training effect.7577 Evidence suggests an functional class and clinical outcomes.86
increase in the level of nitric oxide, a decrease in the level Shockwaves exert a differential effect on resilient and
of endothelin, and an increase in the level of circulating calcified tissues and have been associated with minimal
CD34+ stem cells after EECP therapy.78,79 These changes damage to skin and internal organs, even when used at
lead to improvements in blood pressure, which might high-energy levels (for example lithotripsy for kidney
have a role in the clinical improvement.80 stones)cardiac ESWT typically uses one-tenth of the
The main randomized trial leading to approval of energy dose required for lithotripsy. Electrocardiogram
the technique was MUSTEECP,81 which involved 139 gating on Rwaves avoids impulses during myocardial
patients with advanced CAD and refractory angina, and in repolarization, which could theoretically trigger malig-
which 35h of active counterpulsation was compared with nant ventricular arrhythmias. ESWT is a noninvasive
inactive counterpulsation. No difference was observed in modality that seems to be safe and warrants further study
total exercise duration between the two groups, but time to determine the optimal dose and protocol as well as its
to exercise-induced STdepression increased signifi- efficacy in patients with refractory angina.
cantly (P=0.01) and angina was less frequent (P<0.05)
in patients receiving active counterpulsation. 81 EECP Invasive therapies
is contraindicated in patients with decompensated HF, Recanalization of chronic total occlusion
severe peripheral artery disease (including abdominal Chronic total occlusions (CTOs) are now success-
aortic aneurysm), or severe aortic insufficiency.73,74 EECP fully recanalized in up to 90% of appropriately selected
(35 1h sessions over 7weeks) is approved and reimbursed patients.87 Investigators in observational studies have
in the USA and parts of Europe for the management of reported improvements in long-term outcomes,88 but
CCS classIII and IV refractory angina. few have reported the effect on angina.8991 PCI has not
been directly compared with medical therapy for CTO,92
Extracorporeal shockwave therapy although two large trials, the DECISIONCTO (n=1,300)
In low-energy extracorporeal shockwave therapy and EUROCTO (n=1,200) trials, were initiated in
(ESWT), a generator system focused with echographic 2010and 2013, respectively, to address this issue.

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In a meta-analysis of nonrandomized studies per- 100


P <0.05
formed before the era of drug-eluting stents, outcomes
after successful or failed CTO PCI were compared. 93 80
Successful
Successful recanalization (n=1,581) was associated Failed
with a reduction in residual or recurrent angina at

Population (%)
1236months (OR0.45, 95%CI 0.300.67), 93 and 60
Olivari and colleagues reported that patients with a suc-
cessfully recanalized CTO were more likely than those 40
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, 20
those with successful recanalization (n=237) experi-
enced less limitation in physical activity, fewer anginal
0
episodes, and improved treatment satisfaction than those
Once per day Once per week <Once per week
with failed PCI (Figure4).94 Angina frequency
By contrast, similar proportions of patients with suc-
cessful or failed CTO recanalization self-reported angina Figure 4 | Successful percutaneous coronary intervention
for chronic total occlusion is associated with reduced
(20% versus 24%; P=0.50) and good-to-excellent quality
angina frequency. The majority (87%) of patients who were
of life (73% versus 68%; P=0.52) at 6months after the successfully recanalized experienced angina symptoms
procedure.90 In the FACTOR trial,89 a successful CTO PCI less than once per week, compared with 56.5% of patients
was independently associated with improvement in symp- with failed recanalization. Reprinted from Int. J. Cardiol.
toms, function, and quality of life in symptomatic patients, 161(1) Borgia, F. etal. Improved cardiac survival, freedom
but the small sample size (n=125), underutilization of from MACE and angina-related quality of life after
antianginal medication in patients with failed PCI, and successful percutaneous recanalization of coronary artery
chronic total occlusions. 3138 2012, with permission
number of patients excluded from the analyses (n=23)
from Elsevier.
complicate the interpretation of the results.
CTO PCI is not without complications, including
MI, perforation, and death, and can lead to micro- Therapeutic angiogenesis
vascular plugging and distal bed embolization. 95 PCI The use of protein growth factors, gene therapy, or
itself has no effect on outcomes in patients with stable stem-cell therapy to enhance the natural process of
CAD, with limited improvement in angina, 96,97 which angiogenesis has been termed therapeutic angiogenesis.
raises questions about the large effect size reported These techniques are supported by successful preclinical
with successful CTO PCI.98 Current practice guidelines studies in the setting of ischaemic myocardium.106108
recommend CTO PCI for patients who are unsuit-
able for CABG surgery, remain symptomatic despite Protein and gene therapy
optimal medical therapy, and have a documented large Two large, randomized, placebo-controlled trials involv-
ischaemicburden.99,100 ing intracoronary VEGF and fibroblast growth factor
(FGF) showed no efficacy in terms of the primary end
Reduction of the coronary sinus point (exercise time), but positively affected the second-
Percutaneous reduction of the coronary sinus is a con- ary end points (angina and quality of life) in patients
temporary adaptation of a principle originally described with angina.16,17 A short half-life was thought to be the
by Beck and Leighninger, who performed surgical nar- major limitation for the angiogenic proteins, which lead
rowing of the coronary sinus to restrict drainage of to an interest in gene therapy in an attempt to prolong
efferent venous blood from the left circulation.101 The the angiogenic stimulus. Intracoronary delivery of an
theory was based on blood-flow redistribution to ischae- adenovirus encoding FGF5 (Ad5FGF) was successful
mic myocardium via a trans-sinusal pressure gradient, in the AGENT 109 and AGENT2110 trials, which lead
creating an imbalance in regional capillary pressure and to two large, phaseIII trials. AGENT3 and AGENT4
allowing for redistribution of coronary arterial blood to were double-blind trials using two different dose groups
underperfused myocardium. Under physiological con (low dose of Ad5FGF4: 1109 viral particles, high dose
ditions, the subepicardial arteries constrict in response of Ad5FGF4: 11010 viral particles) and placebo in
to stress, and redirect blood into the subendocardiuma a 1:1:1 randomization ratio with a primary end point
compensatory mechanism that might be dysfunctional of change in exercise treadmill time from baseline to
in patients with both advanced CAD102 and HF.103 The 12weeks. A pooled analysis of AGENT3 and AGENT4
Neovasc Reducer(Neovasc, Inc., Canada) is a stainless showed no difference in the primary end point, but did
steel, balloon-expandable, hourglass-shaped device that show a significant reduction in angina and a substantial
creates a controlled narrowing of the coronary sinus. The exercise benefit in high-risk patients, defined as those
device was associated with an improvement in ischae- aged >55years, angina classIIIIV, and baseline exer-
mia in a single-arm, phaseI trial involving patients with cise time <300s.18 In two moderately sized (n=80 and
refractory angina, and is currently being studied in the n=93), randomized, placebo-controlled trials, no effect
phaseII COSIRA trial.104,105 of intramyocardial delivery of the gene encoding VEGF

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

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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 promoting the release of aminobutyric acid, which
group than in placebo-treated group (6.81.1 versus antagonizes the effect of the descending inhibitory path-
10.91.2; P=0.02), with a significant improvement in ways that are known to favour the transmission of the
exercise time (139115s versus 69122s; P=0.014).117 nociceptive afference.123 SCS might have a dual effect
These results were sustained at 12months.117 The results on angina. In addition to the analgesic effect described
in the high-dose group were similar to those in the low- above, SCS has been hypothesized to mediate a sympa-
dose group, with no evidence of a doseresponse rela- thicolytic effect, which could indirectly reduce vasocon-
tionship.117 Alarge, phaseIII trial is ongoing, which will striction and myocardial ischaemia.124,125 The association
potentially lead to regulatory approval of CD34+ cells in between SCS, the autonomous nervous system, and
patients with refractory angina.118 Potential future direc- reduction in ischaemia has, however, beeninconsistent.126
tions for cell therapy include delivery via retroperfusion During SCS, the electrode is linked to a programmable
in the coronary sinus,119 and gene-modification of cells to pulse generator with settings customized for each patient.
enhance their cytoprotective and proangiogenic proper- The therapy is self-administered and typically requires
ties,120 as well as allogeneic cells, cardiac-derived cells, or stimulation for 1h, three times per day, and whenever
pluripotentcells.121 angina occurs. SCS has been compared with various
control treatments (such as CABG surgery and percuta-
Neuromodulation neous myocardial laser revascularization) in seven ran-
Neuromodulation is the use of chemical, mechanical, or domized trials. A meta-analysis of these trials showed
electrical means to interrupt a pain signal anywhere in the a significant improvement for patients allocated to SCS
transmission pathway from the periphery to the brain. in terms of exercise capacity (standardized mean differ-
In addition to pain relief, neuromodulation of thedis- ence [SMD]0.76, 95%CI 0.071.46, P=0.03; Figure7),
eased heart has the potential to alter the unfavourable and health-related quality of life (SMD0.83, 95%CI
sympathetic afference responsible for vasoconstriction, 0.321.34, P=0.001). 127 The ESC Joint Study Group
which leads to ischaemia. In particular, neuromodulation on the Treatment of Refractory Angina granted SCS a
seems to be useful for patients with a prominent neuro- classIa recommendation >1decade ago.3 Subsequently,
genic, rather than ischaemic, component to their cardiac the authors of the 2012CCS guidelines for the manage-
pain(Figure6). ment of patients with refractory angina gave a weak
recommendation for the use of SCS to improve exercise
Spinal-cord modulation capacity and quality of life, owing to methodological
Transcutaneous electrical nerve stimulation is a non- concerns about the available evidence.4 In registry data,
invasive option reported to be successful in relieving which tend to reflect real-world practice, SCS has been
angina. This technique is often used temporarily to associated with reductions in both angina frequency and
assess responsiveness to neuromodulation before a nitrate consumption.128 Two small, single-blind trials
moredefinitive measure, such as SCS, is initiated.122 suggested a benefit of SCS,129,130 but investigators in the
SCS has been used for 3decades in a variety of chronic largest blinded trial attempted to date, STARTSTIM,131
pain syndromes. For cardiac pain, a multipolar electrode had difficulty reaching enrolment targets and showed no
is surgically positioned in the epidural space between the difference between active-treatment and control groups,
C7 and T4 vertebrae, near to the dorsal column where both of which showed improvement consistent with a
the myocardial afferent sympathetic fibres synapse with placebo effect. Despite two positive systematic reviews
second-order sensory neurons in the dorsal horns. SCS and the ESC recommendation, SCS is not approved in
is thought to alter the dorsal-horn neurochemistry by 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 safety and feasibility of the concept using a stimulation
Subcutaneous electrical nerve stimulation (SENS) is a protocol of three periods of 1h daily.133 All patients
fairly new method to treat refractory angina, although experienced reductions in the frequency of angina
the technique has been used to treat other chronic pain and sublingual nitrate consumption.133 As with SCS,
disorders.133 SENS targets subcutaneous nerve endings potential interactions between the pulse generator and
located in the precordial regions, from where the angina implantable defibrillators is of concern and warrants
radiates. Multipolar electrodes are subcutaneously additional safety information. If effective, SENS might
implanted in the parasternal area, where patients typi- prove useful for patients who require dual antiplatelet
cally feel anginal pain, and tunnelled to a pulse genera- therapy or anticoagulation, in whom positioning an
tor located in the upper abdomen. In a pilot study of electrode in the epidural space is associated with a high
seven patients, Buiten and colleagues demonstrated the risk of bleeding.

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REVIEWS

SCS Control Mean difference Mean difference


Study or subgroup Mean SD Total Mean SD Total Weight (95% CI) (95% CI)

Jessurun (1999) 14.6 3.2 12 15.3 3.4 12 27.2% 0.20 (1.01 to 0.60)

Hauvast (1998) 19 14 13 0.2 17 12 25.7% 1.20 (0.332.06)

Eddicts (2007) 394 55 12 337 55 12 25.8% 1.00 (0.141.86)

DeJongste (1994) 827 138 8 694 67 9 21.4% 1.19 (0.132.24)

Subtotal (95% CI) 45 45 100.0% 0.76 (0.071.46)

4 2 0 2 4
Favours control Favours SCS
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 with either the low dose or the high dose than in those
The left stellate (cervicothoracic) ganglion is a readily who received placebo (nine patients versus no patients;
accessible point of convergence for sympathetic fibres P=0.03).136 The results of DIRECT136 dampened enthu-
that transmit the afferent cardiac pain signal to the siasm for TMLR, although the two approaches (TMLR
intermediolateral grey column in the thoracic spinal and PTMLR) are not necessarily equivalent. TMLR is
cord enroute to the central nervous system. Temporary contraindicated in patients with a low left ventricular
sympathectomy by stellate ganglion blockade has ejection fraction or recent MI, because morbidity and
been associated with anecdotal success in patients mortality are substantially increased in these patients.4,6,7
withangina, but has never formally been assessed in an
appropriately designed trial. Alternative routes for tem- Patient-centred care
porary (high thoracic epidural analgesia) and perma- Specialized clinics for refractory angina
nent sympathectomy have also been used with varying A multidisciplinary approach is often needed for the
success.134,135 Owing to the lack of appropriate evidence, optimal treatment of patients with refractory angina. In
no practice recommendations can be formulated about addition to physical rehabilitation, physical and occupa-
cardiacsympathectomy.3,4 tional therapy, drug optimization, and aggressive risk-
factor modification, a multidisciplinary team can offer
Transmyocardial laser revascularization advanced options customized to a patients profile.20 The
The development of transmyocardial laser revasculariza- opinions of interventional cardiologists and cardiac sur-
tion (TMLR) was developed according to the theory that geons are crucial to periodical reviews of the suitability
channels in the myocardium would carry blood from the of patients for revascularization in the context of a risk-
ventricular cavity directly to the myocardium, similarly to-benefit ratio modified by a diminished quality of life.5
to those in reptilian hearts.2 However, the mechanism Anaesthesiologists and neurosurgeons can provide input
of benefit is more likely to be the result of injury stimu- into the neuropathic component of refractory angina.
lating angiogenesis or denervation. TMLR is performed Nurses and psychotherapists will complete the pro-
epicardially during a surgical procedure (open chest or gramme with self-management training and reassurance
robotic) or endocardially via a percutaneous approach when appropriate. A multidisciplinary approach includ-
(PTMLR). TMLR, either alone or in conjunction with ing medical and behavioural interventions and physical
CABG surgery, is approved by the FDA for the treatment rehabilitation has been associated with improved health-
of refractory angina. related quality of life,137 enhanced physical ability,138 and
A series of open-chest surgical trials showed improve- reduced hospital readmission.139
ments in angina, exercise time, and myocardial perfu-
sion, but lacked placebo controls for obvious reasons.1214 Mental stress-induced myocardial ischaemia
In the PACIFIC trial,15 PTMLR and medical therapy was Classic angina occurs in response to stress, either
compared with medical therapy alone in 221 patients physical or emotional. Mental stress-induced myocar-
with CCS classIII angina. PTMLR was associated with dial ischaemia (MSIMI) is infrequently diagnosed, but
an improvement in exercise tolerance.15 Unfortunately, might actually be more prevalent than exercise stress-
the only double-blind, placebo-controlled trial of induced myocardial ischaemia.140 In a study involving
PTMLR (DIRECT136), which involved 298 patients (98 participants with stable CAD, MSIMI and exercise-
placebo; 98 low-dose, 1015 channels; 102 high-dose, induced ischaemia occurred in 43% and 34% of the
2025 channels), showed no difference in the primary cohort, respectively (P=0.002).141 Relative to physical
end point (change in exercise duration) at 6month stress, mental stress results in higher heart-rate and
follow-up. All three groups had a significant improve- bloodpressure responses.142
ment in symptoms, highlighting the importance of the Whereas the association between MSIMI and future
placebo effect.136 Additionally, the 30day incidence adverse cardiovascular events is well documented, 140
of MI was higher in the aggregate of patients treated the role of pharmacological interventions targeted at

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

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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.

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