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I. Introduction

Refractory vasospastic angina (VSA) has been defi ned as un-

responsive to two types of coronary vasodilators [typically calci-

um channel blocker (CCB)s and nitrates] at conventional doses

in the Japanese Circulation Society (JCS) guidelines1). The man-

agement of refractory VSA is challenging, and no specifi c rec-

ommendations for this clinical setting exist in cardiologic guide-

lines2). Because refractory VSA may have a risk of sudden

cardiac death3) if appropriate treatment is not given, the manage-

ment with treatment options would be very important (Table 1).

In this narrative review non-conventional treatments for patients

with refractory VSA are provided to broaden the target popula-

tions to be cured. For cases in which conventional drugs cannot

be tolerable due to the severe side effects usually headache4-6),

similar management could be adaptable to the refractory VSA.

II. Prevalence of refractory VSA

According to a research task force by a Ministry of Health,

Labour and Welfare, the incidence of VSA was 40.9%

(921/2,251) of patients with angina in Japan ; 126 of these pa-

tients (13.7%) were intractable7). When atherosclerotic stenosis is

detected in the coronary arteries, VSA is often superimposed 8, 9)

in 51.5-66.7% of patients.

Coronary artery spasms may be refractory to optimal vasodi-

lator therapy, and may require very high doses of calcium chan-

nel blockers (CCBs) /nitrates, in order to manage the vasospastic

‘storm’ in about 10% of cases 10). The ratio of disappearance of

chest pain attacks while receiving medical therapy was only in

38% in 71 patients11). In another study, drug-refractory VSA, de-

fined as VSA not responding to treatment with 2 CCBs plus a

long-acting nitrate, is noted in approximately 20% of patients

with VSA12, 13). These results suggest a limitation of drug therapy.

III. Mechanism and initiation of VSA

A coronary spasm has been reported to be caused by both en-

dothelial dysfunction and vascular smooth muscle hypercontrac-

tion14-16). In the molecular mechanism of VSA, Rho-kinase has

an important role15, 17). The mechanism of coronary spasm may

be multifactorial14, 18). Fig. 1 shows the initiation process of VSA.

Along with intrinsic factors, a combination of risk factors and

triggers may induce coronary spasm, which causes clinical man-

ifestations such as angina pectoris, acute coronary syndrome,

and life-threatening arrhythmia. Smoking, a risk factor1) and ge-

netic polymorphism (-786T/C polymorphism of endothelial ni-

tric oxide synthase19), etc.) are the representative causative fac-

tors. Each patient with VSA may have different causative factors

that can sometimes become treatment targets.

Review Article

Potential Treatments for Refractory Vasospastic Angina

Shigenori Ito1, and Yoshiyuki Shimizu2

Vasospastic angina (VSA) is a common disease that causes rest/effort angina attacks globally. Coronary spasms occur in patients with and without atherosclerotic coronary stenosis based on the underlying causative mechanisms and triggers. The first-line and effective treatments, which are calcium channel blockers and nitrates, have been established as shown in the multiple guidelines. However, it is also well known that some refractory VSA patients do not respond to standard therapy and remain to complain of angina symptom. Furthermore, severe clinical manifestations such as acute coronary syndrome and lethal arrhythmia may occur, which often disturb daily life. Thus, additional personalized treatments for individual refractory VSA patient are mandatory. Although scientific reports with a high level of evidence regarding treatments for refractory VSA are limited, a significant number of reports have been published including case series reports that showed successful empirical treatments. Each therapy might not be appropriate for all patients but may be effective for patients with specific characteristics owing to the mechanism and trigger of spasm. In this review, the optional pharmacological and invasive treatments for refractory VSA are described.

KEY WORDS: coronary spasm, intractable, refractory, treatment, vasospastic angina

1Division of Cardiology, Sankuro Hospital, 7-80, Kosaka-cho, Toyota-shi,

Aichi-ken, 471-0035, Japan, 2Department of Medical Sciences, Faculty of

Health and Medical Sciences, Hokuriku University

E-mail: shigeito918@gmail.com

Received: June 7, 2021; Accepted: July 22, 2021

doi: 10.7793/jcad.27.21-00012

© The Japanese Coronary Association

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Table 1　Summary of Treatments for Refractory Vasospastic Angina

Treatments for Refractory Vasospastic Angina and suspected underlying mechanisms

Standard Pharmacological Treatments (JCS class) Mechanisms Ref

1 Calcium channel blockers (Class I) Inhibit the influx of Ca2+ ion into the vascular SMC 25, 29

2 Nitrates/Long-acting nitrates (Class I/Class IIa) Relax vascular SMC by nitric oxide provider 28, 42

3 Nicorandil (Class IIa) Opens ATP sensitive K channels 45

Optional Treatments

Pharmacological Mechanisms Ref

1 Fasudil chloride (Rho-kinase inhibitor)(Class IIa for intractable VSA)

Inhibits Ca2+non-dependent coronary vasoconstriction 54, 55

2 Corticosteroids (class IIb) Suppress inflammation 57, 61

3 HMG-CoA reductase inhibitor (class IIb) Improves endothelial dysfunction 65, 66

4 Eicosapentoic acid (Raffinee epagold) Inhibits Rho-kinase pathway, suppress inflammation 68

5 Cilostazol Inhibits phosphodiesterase 3 selectively 72

6 Kampo (Japanese herbal medications) Depends on the mixed medicines 73, 78

7 Piogritazone Improves insulin resistance and endothelial dysfunction 80

8 Magnesium sulfate Correct magnesium deficiency 82, 83

9 Denopamine (selective beta 1 adrenoceptor agonist) Corrects autonomic nervous system unbalance 84, 86

10 Bosentan (ET-1 receptor inhibitor) Corrects imbalance in the close interdependence of NO and ET-1 87, 89

11 Alpha 1-adrenergic receptor antagonists Unknown 90, 91

12 antiadrenergic drugs, guanethidine and clonidine Suppress central sympathetic nerve 92

13 Continuous Combined Estrogen-progestin Hormonal Contraception Use (class IIb for menopause women)

Improves endothelial function 93, 94

14 Levosimendan Opens ATP-sensitive K channels in the vasculature 98

15 Valsartan (angiotensin II receptor antagonist) (class IIb) Blocks angiotensin II receptor type 1, antioxidative effect, attenuates nitrate tolerance

100

16 Vitamin C Improves endothelial function as antioxidant 105

17 Vitamin E (class IIb) Antioxidant 106, 107

Non-pharmacological Treatments Mechanisms Ref

1 Coronary stent implantation (class IIa for severe organic stenosis with adequate medications)

Physical vessel dilatation 1, 108

2 Coronary artery bypass grafting Takes a roundabout root 114, 115

3 Left stellate ganglion block Blocks sympathetic nervous system 119, 120

4 Surgical endoscopic cardiac sympathectomy Cardiac sympathetic denervation (plexectomy) 124

5 Renal sympathetic denervation Potential decrease of intra-cardiac SNS 126

6 Implantable cardioverter defibrillator (ICD) Prevents spasm-induced lethalarrhythmia 1, 129, 130

JCS: Japanese Circulation Society, Ref: reference, SMC: smooth muscle cell, ATP: adenosine triphosphate, HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A, ET: endothelin

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IV. Characteristics of refractory VSA

The patients with refractory VSA were characterised as

younger, with a higher ratio of smoking and normotensive than

non-refractory VSA patients1, 11) and had a longer history of chest

pain attacks before hospital admission11). Angiographic diffuse

spasms were detected with a high incidence in the spasm provo-

cation test in the refractory VSA patients who required second

drugs (nitrates or nicorandil) after the administration of long-act-

ing CCBs11). Meanwhile, another study reported that diffuse

spasm has a better prognosis than does focal spasm20).

V. Pharmacological treatments of refractory VSA

Smoking cessation efforts are essential and mandatory before

pharmacological treatments in patients with refractory VSA21, 22).

Additionally, aerobic exercise training has been shown to reduce

angina episodes in patients with VSA23). The treatment strategy

of VSA is proposed in Fig. 2. The mainstay of treatment for cor-

onary vasospasm is CCB and nitrates ; however, the responses

to treatment can be variable10). Although the managements of re-

fractory VSA involves both pharmacological and non- pharma-

cological therapies24), non-pharmacological therapies are usually

adopted only in cases refractory to medical treatments.

1. Conventional drugs

CCBs

CCBs have been widely used as the fi rst-line drugs; they sup-

press VSA attacks and improve the outcome of patients with

VSA25-27). For the prevention of VSA attacks, CCBs are found to

be effective in approximately 93% of patients; dihydropyridine

CCBs have greater efficacy than non-dihydropyridine ones24).

The other reports showed that the effi ciency of CCBs for VSA

varies among different drugs28, 29). Benidipine had the highest

coronary artery selectivity and was more effective in treating

VSA30, 31). The hazard ratio for the occurrence of major adverse

cardiovascular events was signifi cantly lower in patients treated

with benidipine among the four CCB groups, even after correc-

tion for patient characteristics29). Thus, if one CCB is not effec-

tive in treating VSA angina, several counter parts should be con-

sidered18). The following recommendations during CCB use

might be helpful for refractory or intolerant cases: 1) A change

or combination in the CCB type (dihydropyridine CCB and

non-dihydropyridine CCB)32, 33), 2) higher-dose CCBs than sub-

maximal or maximal dose/once or twice a day10) (verapamil or

diltiazem 960 mg/day and/or nifedipine 100 mg/day and ni-

trates34-36)), 3) change from once-a-day CCB to twice a day to

prevent the attacks just before the dosing time, 4) prescribing

CCB at bed time to prevent attacks between midnight and early

morning14, 37), and 5) an occasional switching from generic CCBs

to branded ones38).

Nitrates

Nitrates compensate for the reduced nitric oxide (NO) activity

recognized in patients with VSA39). The effi cacy rate increases if

CCB and nitrates are combined, to nearly 100%27, 28, 40, 41), where

long-acting nitrates are preferred27, 28, 40, 41). It should be noted that

chronic nitrate therapy did not improve the long-term prognosis

of VSA patients when combined with CCBs42). Furthermore, use

of multiple nitrates was an increased risk for cardiac events42). To

prevent resistance to nitrate, which occurs owing to the constant

Fig. 1　The pathophysiology, risk factors, triggers, and clinical manifestations of coronary artery spasm.The cause of vasospastic angina is multifactorial. The treatment strategy can be derived from patho-physiology, risk factors, and triggers.VSMC: vascular smooth muscle cell, CNS: central nervous system, ACh: acetylcholine

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blood concentration of nitrates, a drug suspension period would

be recommended.

Nicorandil

Nicorandil is a derivative of nicotinic acid amide and exerts

two distinct anti-angina mechanisms, acting as both: (1) NO do-

nor, and (2) adenosine triphosphate-sensitive potassium channel

opener43, 44) providing a selective coronary vasodilation and an-

ti-vasospastic action45). The efficacy of nicorandil on coronary

spasm has been evaluated with good effectiveness46-48) either as

single drug or in combination with other drugs. Nicorandil is

classifi ed as a class IIa drug for VSA in the JCS guideline and

should be reminded as a proposed therapy in patients with re-

fractory VSA. It should be noted that there was a report that

showed unfavourable results for long-acting nitrates and a com-

bination of nitrates and nicorandil42).

2. Optional drugs

The trying out of multiple options would be reasonable way to

explore the potentially effective treatments to the suspected

mechanisms, although it must be noted that each medication is

only mentioned on case series -basis and is not covered by insur-

ance for VSA. First, before adopting unusual drugs, an increase

of the CCBs with or without a combination of nitrates should be

considered. Often, the intravenous administration of CCBs and

nitrates could be attempted .

Rho kinase inhibitor

Reduced endothelial NO activity results in an increased Ca2+

sensitivity through the enhanced Rho A/ Rho-associated protein

kinase pathway49-52). Rho A/ Rho-associated protein kinase path-

way blockers may be useful to treat patients with coronary

spasm through the inhibition of Ca2+non-dependent coronary va-

soconstriction53, 54). Fasudil (Y-27632), a selective Rho-kinase in-

hibitor, effectively prevented ACh-induced coronary artery

spasm55) and was also effective in clinical settings to treat refrac-

tory VSA after coronary balloon angioplasty54) and coronary ar-

tery bypass grafting56). However, adequate evidence has not yet

been accumulated for fasudil in the treatment of VSA, because it

has not been widely utilised for VSA .

Corticosteroid

Corticosteroids was effective in treating patients with refracto-

ry VSA, who had allergic disease (e.g. bronchial asthma, chronic

thyroiditis, and Raynaud phenomenon)46, 57), hypereosinophil-

ia58-61), and adventitial focal inflammatory cells infiltration62).

The anti-infl ammatory effects may contribute to the control of

vasospastic angina63). The initial dose of oral prednisolone for

the treatment of refractory VSA is controversial without guide-

lines ; three case reports have suggested that it should be 20–40

mg/day46, 57, 63). The use of corticosteroids should be considered

carefully only in selected patients with refractory VSA associat-

ed with allergic disease because of the adverse side effects 63).

The maintenance dose must be determined carefully on a case-

by-case basis58) to prevent recurrence during the process of de-

creasing the dosage64).

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibi-

tors (HMG-CoA reductase inhibitor)

In vitro and in vivo studies indicated the benefi cial effects of

the statins (HMG-CoA reductase inhibitor) unrelated to cholester-

Fig. 2　Treatment strategy of refractory vasospastic angina.The fi rst-line treatment is calcium channel blockers with and without nitrates. Refractory cases of vasospastic angina require additional treatments including pharmacological and non-pharmacological (invasive) modalities. The ratio of symptomatic VSA is expected to decrease along with optional treatments.ICD: implantable cardioverter defi brillator

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ol lowering via endothelial NO or by direct effects on the vascular

smooth muscle: improving the endothelial function, increasing

myocardial perfusion, and enhancing the availability of NO52, 65).

A statin (fluvastatin®30 mg/day) suppressed acetylcholine-in-

duced coronary spasm66) and reduced cardiovascular events65).

There have been no other reports to evaluate the effects of a statin

on naturally occurring spasm attacks in patients with refractory

VSA. It is not known whether this effect is a class effect of statins

or not. The possible drug interactions of fluvastatin® with CCBs

were the lowest and its vascular effects were highest among the

statins clinically available 67).

Eicosapentaenoic acid (EPA)

EPA, an omega-3 polyunsaturated fatty acid, health supple-

ment Raffinee-epagold® (Orientalbio Co., Ltd., Tokyo, Japan)

was effective in reducing spasms in a 52-year-old man with

VSA68). He was intolerant to vasodilators due to severe head-

aches. Although he managed to tolerate only 200 mg of dilti-

azem hydrochloride R per day, the concomitant use of other

medications was not feasible. The potential add-on effect of

Raffinee-epagold® (3 tabs per day which contains EPA: 302 mg,

docosahexaenoic acid (DHA): 84.0 mg, vitamin E: 14.1 mg, vi-

tamin C: 14.4 mg, vitamin B12: 1.2 μg) was shown on this pa-

tient by the reduction of frequency in angina attacks and use of

nitroglycerin as needed68). Shirano and Kobayashi., et al. previ-

ously reported that EPA inhibits sphingosylphosphorylcho-

line69)-induced Ca2+-sensitisation of vascular smooth muscle con-

traction by targeting Src family protein kinases without any

influence on the intracellular Ca2+ concentration that normalises

vascular contractions70). Raffinee-epagold® is expected to act as

another inhibitor of the Rho-kinase pathway and might be ad-

vantageous to prevent coronary spasm by improving the endo-

thelial function70).

Cilostazol

Cilostazol, an antiplatelet aggregation inhibitor, acts as a se-

lective inhibitor of phosphodiesterase 3 and is associated with

not only increased cerebral blood flow and inflammation sup-

pression but also induction of vascular dilatation. Cilostazol (200

mg/day) may significantly suppress cerebral vasospasm follow-

ing subarachnoid hemorrhage71). The addition of cilostazol to a

CCB (amlodipine) decreased the frequency and severity of coro-

nary spasm in patients with VSA72). Cilostazol might be an effec-

tive therapy for patients with VSA uncontrolled by conventional

amlodipine therapy.

Japanese traditional herbal medicines (Kampo)

It is often difficult to control chest symptoms in VSA patients

with mental stress73, 74). Shigyakusan has potential effects in pa-

tients with VSA who are associated with psychosomatic symp-

toms, including the malfunction of the autonomic nervous sys-

tem expressed as “kankiukketsu” in Kampo, irritability,

depression, severe-nervousness, and hysterical sensation73).

“Oketsu” is a condition that is particularly emphasised in orien-

tal medicine and is considered to consist of erythrocyte factors

including membrane charge and deformability, blood viscosity,

thrombocytic agglutinability75), and endothelial function76). Keis-

hibukuryogan (KBG) revealed anti-Oketsu effects by endothelial

NO production75). It is possible that KBG has the potential to im-

prove VSA symptoms by improving endothelial dysfunction77).

The combined use of shigyakusan and keishibukuryogan was

effective in two patients with refractory VSA73) . In Case 1, the

addition of shigyakusan (5 g/day) and keishibukuryougan (5 g/

day) to benidipine chloride 8 mg, isosorbide mononitrate 40 mg,

and nicorandil 15 mg/day completely relieved the symptoms af-

ter 3 months. In case 2, Low-dose of Shigyakusan and keishi-

bukuryogan were added to benidipine chloride 8 mg, isosorbide

mononitrate 40 mg, and nicorandil 15 mg/day. One month later,

the symptoms decreased to one-third and completely resolved 3

months after the start of Kanpo. Saibokutou, Hangekoubokutou,

and Mokubouitou were also reported to be effective in reducing

angina attacks and/or use of vasodilative drugs for suspected re-

fractory VSA78, 79). In these cases, definite ischemic electrocar-

diographic changes during attacks were not detected. Kampo

could be used as a support for evidence-based standard therapy

to decrease symptoms.

Pioglitazone

Insulin resistance is associated with endothelial dysfunction,

which is associated with VSA14, 37). A peroxisome proliferator-ac-

tivated receptorγ(PPAR-γ) agonist, pioglitazone (15-30 mg/

day), significantly suppressed coronary spasm in a study of 73

consecutive patients with VSA when added to CCBs (pioglita-

zone group) compared with CCBs alone (control group) for 6

months (50.0% vs 21.6%)80). It could be expected that pioglita-

zone might have additive effects in refractory VSA cases with

insulin resistance.

Magnesium

Magnesium deficiency was shown to be a cause of coronary

spasm in alcohol-induced variant angina81). Magnesium sulphate

(0.27 mM/kg body weight) infusion suppressed hyperventila-

tion-induced coronary spasm significantly in patients with vari-

ant angina82), when infused during a 20-minute period 50 min

before the hyperventilation test. The spasm induction rate was

100% in control and 30% in magnesium infusion group82). Addi-

tionally, magnesium intravenous infusion reduced the severity of

chest pain and ST-segment deviations of spasms during the ace-

tylcholine (ACh) provocation test83). Magnesium could be a po-

tential option to suppress spasm attacks in patients with refracto-

ry VSA83) ; however, the oral intake of magnesium for chronic

VSA has not be investigated yet.

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Denopamine (selective beta 1 adrenoceptor agonist)

Denopamine was effective in suppressing active vasospastic

angina in 10 patients without obstructive coronary artery steno-

sis84, 85). Denopamine (40 mg/day) completely abolished the at-

tacks in 70% and reduced the mean daily number of anginal at-

tacks and nitroglycerin consumption significantly compared with

control. The aggravation of anginal attacks was not observed in

any patient. No severe adverse effects were observed during de-

nopamine therapy. Even low-dose denopamine (15 mg/day) was

effective in a patient with VSA refractory to intensive medical

treatment86).

Bosentan (endothelin-1 receptor inhibitor)

Endothelin-1 (ET-1) was identified as the first endotheli-

um-derived contracting factor87). An increased coronary flow re-

serve and less frequent and less severe chest pain were observed

in patients with severe coronary vasospasms. after 16 weeks of

additional treatment with bosentan88). Bosentan was started at

62.5 mg twice a day during the first month followed by increase

to 125 mg twice a day. Upon completion of the eighth-month

treatment with bosentan, hospitalisation due to angina attack or

acute coronary syndrome was abolished89). Correction of an im-

balance in the close interdependence of NO and ET-1 was specu-

lated as the working mechanism87).

Alpha 1-adrenergic receptor antagonists

Little evidence is available to support the systematic use of al-

pha 1-adrenergic receptor antagonists in the treatment of patients

with VSA ; studies showed conflicting results on this adaptation,

and enrolled numbers of patients were small90, 91). However, it

could be considered as an additional therapy in patients with re-

fractory VSA.

Guanethidine and clonidine (antiadrenergic drugs)

Frenneaux et al. showed that the combined use of guanethi-

dine and clonidine relieved refractory variant angina92). These

drugs work for spasm through the suppression of the central

sympathetic nerve.

Oestrogen replacement therapy in postmenopausal women

Oestrogen improves the endothelial dysfunction, which has

been considered as a pathogenesis of coronary spasm37). It was

shown that anginal attacks with ST segment elevation induced

by hyperventilation were suppressed in all 15 menopausal pa-

tients (mean age 54.2 years) with variant angina after 2-day

transdermal estradiol supplementation (4 mg)93). The supplemen-

tal estradiol augmented flow-mediated endothelium-dependent

dilatation in association with significant elevation of estradiol

level93). It should be noted that the combination of medroxypro-

gesterone acetate, which is used to remove the endometrial-car-

cinogenic effect of oestrogen replacement therapy, with estradiol

might be ineffective for the treatment of VSA due to attenuation

of estradiol effects on endothelium-dependent vasodilation in

postmenopausal women94).

Levosimendan

Levosimendan is a calcium sensitiser and adenosine triphos-

phate (ATP)-dependent potassium- channel opener. It was origi-

nally developed as an inodilating drug for the treatment of acute

heart failure95, 96). It also induces vasodilation in coronary arter-

ies97). Levosimendan was successfully utilized for repeated acute

episodes of pulmonary oedema, and cardiogenic shock, second-

ary to significant mitral regurgitation, caused by myocardial

ischemia due to refractory coronary spasm despite the treatment

with maximal tolerated intravenous CCB and nitrates98). It is no-

table that dysfunction of these channels has been shown to be in-

volved in VSA99).

Valsartan [angiotensin II receptor type 1(AT1 receptor) an-

tagonist]

A drug-refractory case of VSA with multi vessel spasm was

successfully treated with valsartan as an add-on drug (daily dose

of 80 mg followed by 160 mg) associated with regular antiangi-

nal and antioxidative medications (maximum daily doses of iso-

sorbide mononitrate (40 mg), diltiazem (200 mg), and tocopher-

ol nicotinate (300 mg)100). The effect of valsartan was confirmed

by the re-occurrence of the attacks with the same frequency after

stopping valsartan. Valsartan was adopted because of its high

AT1 receptor selectivity101) and an indirect angiotensin II receptor

type 2 stimulation effect102). AT1 receptor blocking and antioxida-

tive effects103), and/or the attenuation of nitrate tolerance104) might

have contributed to the beneficial effect of valsartan on a VSA

patient.

Vitamin C

The effect of vitamin C, an antioxidant, on the abnormal vaso-

motor reactivity in the spastic coronary arteries was evaluated

during the ACh provocation test. Intracoronary infusion of vita-

min C (10 mg/min) infusion suppressed the constrictive response

of the epicardial diameter to ACh in spastic arteries, but no sig-

nificant effect on the control arteries105). The studies that evaluate

vitamin C as therapies to prevent coronary spasm are warranted

in a practical setting as intravenous infusion and/or oral adminis-

tration.

Vitamin E

An association between vitamin E (major endogenous antioxi-

dant) deficiency106)/actual consumption107) and coronary artery

spasm has been suggested and the addition of vitamin E acetate

(300 mg/day) significantly elevated the plasma alpha-tocopherol

levels and inhibited the occurrence of angina in six patients with

active variant angina , who had anginal attacks while receiving

CCBs106).

VI. Non-pharmacological treatments of refractory VSA

If chest pain cannot be decreased/resolved even after some

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optional drugs, the next step could be the non-pharmacological

step.

1. Coronary stent

Percutaneous coronary intervention (PCI) should be avoided

fundamentally besides cases that have no other medical treat-

ments for unbearable symptoms. Even in this case, the stent

might be at least transiently effective in reducing chest pain ;

however, there is no evidence of long-term improvement in the

prognosis36, 108). PCI performed in combination with adequate ad-

ministration of coronary dilators is Class IIb (neither the benefits

nor the efficacy of a method of evaluation or treatment has been

well established) for vasospastic angina with severe organic ste-

nosis in the JCS guidelines1). Meanwhile, PCI performed for va-

sospastic angina without severe organic stenosis is determined as

class III (useless and possibly harmful at times, or its harmful-

ness has been widely agreed upon)1).

The following features of spasms may deny the stent use for

spasm: 1) spasms in multiple vessels in patients with variant an-

gina pectoris109), 2) diffuse or site-changing spasm , 3) stent-in-

duced spasm and neoatherosclerosis as the dark side of bare-met-

al and drug-eluting stents110). Care for spasm would be mandatory

even after stent implantation for fixed stenosis because of spasm

superimposed on fixed atherosclerotic lesions8, 9, 111-113), stent-in-

duced spasm, and neoatherosclerosis.

2. Coronary artery bypass grafting (CABG)

CABG were considered for variant angina previously ; a fo-

cal, non- diffuse atherosclerotic site of VSA was an essential de-

terminant to adopt this invasive treatment 114, 115). However, coro-

nary stenting may represent an alternative treatment option for

only refractory cases. The adoption of CABG should be careful-

ly decided after considering the risk and benefits because CABG

itself might cause refractory spasm in the grafts.

3. Stellate ganglion block (SGB)

Hyperactivity of the sympathetic nervous system (SNS) ele-

vates adrenergically mediated coronary vascular tone, which re-

sults in coronary artery flow reduction116). SNS, when it provides

lasting increased sympathetic activity worsened by mental stress,

was shown to be the pathogenesis of VSA. Considering its work-

ing mechanism117, 118), SBG could be an effective treatment op-

tion for coronary vasospasms119, 120), particularly when angina at-

tacks are related to an increased sympathetic nervous tone:

frequent occurring in the daytime and induction by physical ac-

tivity. Daily repetitions of SBG blocks might have abolished the

vicious circle of the hyper tonus of central nervous system ;

practically, the occurrence of angina attacks could be prevented

in more than one year after stopping SBG blocks120). Left-side

SBG121, 122) was used in cases where VSA was successfully pre-

vented. Complications of SGB are rare but can be life-threaten-

ing in cases of inadvertent subarachnoid or intra-arterial injec-

tion123).

4. Surgical endoscopic sympathetic denervation

Surgical endoscopic thoracic sympathetic denervation re-

vealed a significant reduction in the number of angina episodes

and ST-segment deviation on 24 h Holter monitoring in patients

with refractory VSA124). Cardiac sympathetic denervation (plex-

ectomy) was useful to reduce the frequency of recurrent variant

angina, if added to coronary artery bypass grafting compared

with coronary artery bypass grafting alone in patients with vari-

ant angina125).

5. Percutaneous renal sympathetic denervation (RDN)

RDN, a percutaneous treatment that significantly lowers the

blood pressure and sympathetic nerve activity in patients with

hypertension, might provide additional angina relief in patients

with VSA demonstrating pleiotropic effects126). Thoracic sympa-

thectomy for severe refractory multivessel coronary artery spasm

was effective in a case complicated with ventricular fibrilla-

tion127).

6. Implantable cardioverter defibrillator (ICD)

Although ICD cannot suppress coronary spasm itself, it can

prevent sudden death due to spasm-induced ventricular fibrilla-

tion/ventricular tachycardia3). To date, there are no recommenda-

tions for ICD implantation for primary prevention in patients

with VSA. A history of out-of-hospital cardiac death is a strong

predictor of cardiovascular events in patients with VSA128). The

use of ICD may be considered as a treatment option along with

sufficient and reliable medications for the secondary prevention

of cardiac arrest and in patients who survived from out-of-hospi-

tal cardiac arrest and in those who had an induced coronary

spasm during a spasm provocation test1, 129, 130)

VII. Limitations

It is notable that several reference articles showed empirical

treatments without adequate scientific evidence. Thus, further

accumulated data would be necessary to evaluate the effective-

ness of their treatments. None the less, this review may provide

information regarding treatments options for refractory VSA

cases with no other available choices.

VIII. Conclusion

Refractory VSA is notable and needs to be treated in a poten-

tial way explored among various types of treatments. This review

provides the currently available pharmacological and invasive

treatment options that are based on the suspected mechanisms of

VSA.

Sources of funding

None.

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─ 79 ─

Conflicts of interest

The authors have no conflict of interest for this article.

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