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Abstract

Vasospastic angina is a diagnosis of exclusion that manifests with signs and symptoms, which overlap with obstructive coronary artery disease, most often ST-segment elevation myocardial infarction. The pharmacotherapy that is available to treat vasospastic angina can help ameliorate angina symptoms. However, the etiology of vasospastic angina is ill-defined, making targeted pharmacotherapy difficult. Most patients receive pharmacotherapy that includes calcium channel blockers and/or long-acting nitrates. This article reviews the efficacy and safety of the pharmacotherapy used to treat vasospastic angina. High-dose calcium channel blockers possess the most evidence, with respect to decreasing angina incidence, frequency, and duration. However, not all patients respond to calcium channel blockers. Nitrates and/or alpha₁-adrenergic receptor antagonists can be used in patients who respond poorly to calcium channel blockers. Albeit, evidence for use of nitrates and alpha₁-adrenergic receptor antagonists in vasospastic angina is not as robust as calcium channel blockers and can exacerbate adverse effects when added to calcium channel blocker therapy. Despite having a clear benefit in patients with obstructive coronary artery disease, the benefit of beta-adrenergic receptor antagonists, statins, and aspirin remains unclear. More data are needed to elucidate whether or not these agents are beneficial or harmful to patients being treated for vasospastic angina. Overall, the use of pharmacotherapy for the treatment of vasospastic angina should be guided by patient-specific factors, such as tolerability, adverse effects, drug–drug, and drug–disease interactions.

Keywords

vasospastic (Prinzmetal’s) angina vasospasm calcium channel blockers long-acting nitrates

Introduction

In 1959, Myron Prinzmetal identified a form of angina pectoris that differed in typical symptomatology and electrocardiographic characteristics.¹ Unlike typical angina associated with atherosclerotic heart disease, characterized by pain provoked by exertion and relief with rest, and ST-segment changes (elevation/depression), this “variant” form occurs usually at rest and is most often associated with ST-segment elevation.¹ Today, this type of angina is referred to as Prinzmetal angina or vasospastic angina. In the United States, ∼4% of patients who undergo coronary angiography are found to have at least 1 area of coronary artery vasospasm; however, in Japan, this has been recorded in up to 40% of patients.^2,3 Additionally, compared to caucasians, Japanese patients are found to have a 3-fold higher incidence of multivessel spasms.⁴ It has also been found that males have a higher prevalence of vasospastic angina likely related to a higher prevalence of cardiovascular risk factors.^5,6 Symptoms associated with vasospastic angina are typically first experienced midlife.^6
–8 Overall, patients with vasospastic angina experience frequent episodes of angina; however, with appropriate medical therapy and smoking cessation, patients usually have a good prognosis.^5
–7

Conversely, intolerance or nonadherence to pharmacotherapy and chronic tobacco abuse can significantly decrease survival.^9,10 Furthermore, patients with vasospastic angina and multivessel atherosclerotic disease have a lower survival rate compared to individuals with vasospastic angina and single-vessel disease.¹¹ The Coronary Artery Spasm as a Frequent Cause for Acute Coronary Syndrome (CASPAR) trial demonstrated that patients with acute coronary syndrome (ACS) without obstructive coronary artery disease (CAD) had a better prognosis than those with evidence of obstruction.¹² While little evidence is available for medical treatment of vasospastic angina, there are viable pharmacotherapeutic options used to treat spasms and improve quality of life. The purpose of this article is to provide a comprehensive review of the pharmacotherapy used to treat vasospastic angina.

Pathophysiology

Vasospastic angina is characterized by spontaneous episodes of angina due to reversible constriction of a focal segment or segments of the coronary artery.¹³ Commonly, coronary artery constriction is found at a localized segment of an epicardial coronary artery (focal spasm). However, 2 or more segments of the same vessel (multifocal spasm) or different epicardial coronary arteries (multivessel spasm) may be involved as well.^13
–15 The mechanism for these pathophysiological phenomena is unknown and has been speculated to be related to genetic and environmental factors.³ There are 3 theories postulated as the underlying genetic cause of vasospastic angina, which include:

endothelium dysfunction via a defect in the endothelial production of nitric oxide leading to a decrease in vasodilation and/or a defect in calcium signaling, ultimately causing inappropriate smooth muscle contraction;

abnormal platelet activation triggering coronary artery spasms caused by increased formation of vasoconstrictors, such as thromboxane A₂, serotonin, histamine, and endothelin; and

upregulation of alpha-adrenergic receptor activity.^1,14
–16

Overall, these mechanisms play a role in the pathophysiology of vasospastic angina with an underlying imbalance between vasodilators and vasoconstrictors in epicardial coronary arteries.^16

–20 Microvascular angina may overlap with vasospastic angina due to reduced coronary blow flow to direct arteriolar vasodilators resulting in vasoconstriction of small coronary vasculature. Furthermore, a blood steal phenomenon may occur in microvessels leading to microvascular ischemia. Microvascular vasoconstriction may decrease vasodilator response to exercise causing exercise-induced angina and/or a decrease in myocardial blood flow causing angina at rest.²¹ Additionally, it has been shown that patients with obstructive CAD (≥70% occlusion of vessel) are predisposed to future vasospastic attacks. Studies have demonstrated that up to 60% of patients with obstructive CAD may develop vasospastic angina.²² Moreover, evidence suggests the involvement of the autonomic nervous system.^16

–20 Reduced parasympathetic tone and enhanced reactivity of the alpha-adrenergic vascular receptors play an important role in vasospastic angina pathophysiology. This interplay may explain the mechanism behind the risk of spasms being transient yet recurrent.^16,23

–26

The spectrum of presentation is variable, ranging from angina with minimal exertion (or even at rest) to the development of myocardial infarction as a result of vasospasm. Chest pain can occur due to atherosclerosis in this population; however, the narrowing of the coronary vasculature plays a primary role in the development of angina.^17
–19

Diagnosis

Diagnosis of vasospastic angina is often difficult, given the transient nature of this disease. Noninvasive methods of diagnosing vasospastic angina that are most commonly used include 12-lead electrocardiography (ECG) during an attack, use of Holter monitors, and exercise testing.¹³ Noninvasive methods are typically coupled with administration of coronary vasodilators such as nitroglycerin or calcium channel blockers (CCBs).²⁰ Alleviation of symptoms and ECG abnormalities may help guide practitioners toward the diagnosis of coronary vasospasm. Additionally, patients’ demographics and symptomatology can facilitate the clinician’s ability to diagnose vasospastic angina. Both age and sex play a role in the development of vasospastic angina. Specifically, younger female patients are more likely to experience vasospastic angina, despite the absence of atherosclerotic risk factors seen in typical angina patients.²⁰ Vasospastic angina presents as chest pain which is similar to that of stable exertional angina. It may be accompanied by cold sweats, nausea, or vomiting and rarely syncope.¹⁰ It may also be precipitated by exposure to cold and rapidly resolved with sublingual nitrates and CCBs.²⁰ During exacerbations, patients most often have ST-segment elevation on ECG.²⁰

Risk Factors and Etiology

Risk factors for the development of coronary artery vasospasms include the use of nicotine-containing products, hypomagnesemia, alcohol consumption, and illicit drug use. Agents that have the potential to induce vasoconstriction may exacerbate coronary artery spasms. These agents include antimigraine agents (eg, triptans) and chemotherapy (eg, 5-fluorouracil, capecitabine) as well as cocaine, marijuana, amphetamines, alcohol, and ephedrine-based weight-loss products.²⁷ Nicotine is a vasoconstrictor that can also induce or exacerbate coronary atherosclerosis.²⁸ Miwa et al reported that smoking cessation significantly reduced the incidence of patient-reported angina episodes.²⁹ Thirty-seven patients with vasospastic angina were treated with a nondihydropyridine CCB and counseled on smoking cessation. Angina was significantly higher in those who continued to smoke at 3-month follow-up (62% vs 21%).

Pharmacotherapy of Vasospastic Angina

Evidence surrounding the various pharmacotherapeutic options for vasospastic angina is limited. The 2014 non-ST-segment elevation ACS (NSTE-ACS) guidelines provide recommendations that will be recapitulated throughout this review.³⁰ Table 1 provides a summary of the literature discussed for each agent. Before initiating pharmacotherapy, risk factor modification should be taken into consideration. For instance, smoking cessation is one of the most compelling risk factors that can be modified. When pharmacotherapy is used, the clinician must consider patient-specific factors such as drug–drug interactions, drug–disease interactions, and adverse effects when selecting agents to treat vasospastic angina. Please refer to Figure 1 for a summary of medication management in vasospastic angina.

Table 1.

Agents Commonly Used in Vasospastic Angina.^a,b

Drug Class		Clinical Trial	Agent(s)	Principle Outcome of Interest	Implications
First line	Non-DHP CCB	Rosenthal, et al.³¹ n = 48	Diltiazem IR 120 mg/d or Diltiazem IR 240 mg/d	Decreased frequency of angina (P < .005 for 120 mg; P < .01 for 240 mg)	Diltiazem is a safe and effective agent for symptom control of vasospastic angina that decreases the frequency of angina
	DHP CCB	Antman, et al.³² n = 127	Nifedipine ER 40-160 mg daily	Decreased frequency of angina attacks (P < .001)	Nifedipine significantly decreases the amount of SL NTG tablets used per week, decreases the frequency of angina attacks, and the amount of angina attacks per week; long-term efficacy needs to be elucidated.
	DHP CCB	Schick, et al.³³ n = 38	Nifedipine IR 63.2 + 6.4 mg	Reduced number of angina attacks per week (P = .02). Reduced number of NTG tablets used per week (P = .01)
	Non-DHP/DHP CCB	Freedman, et al.³⁴ n = 37	Verapamil IR 120-600 mg/d or Nifedipine IR 30-80 mg/d	Significantly more patients receiving verapamil at lower doses required dose increases (P < .01). Reduced recurrent angina (P < .02 for smokers; NS for nonsmokers); adverse events (NS)	Long-term treatment with a non-DHP or DHP CCB appears to be well tolerated, lacked serious adverse events, relieved angina, and is associated with significantly less recurrence of angina in smokers
Second line	Nitrates	Conti et al.³⁵ N = 19	10 mg sublingual nifedipine and 200 μg nitroglycerin intracoronary infusion	Nifedipine/nitroglycerin dilated more coronary arteries compared to nifedipine alone (P < .01).	Nitrates, in combination with CCBs, may vasodilate arteries synergistically, producing an additive effect. This combination may improve symptomatic coronary vasospasm and decrease incidence of coronary vasospasm, without serious adverse effects. However, nitrates do not appear to have a long-term prognostic benefit
		Freedman et al.³⁴ N = 37	Verapamil 120-600 mg/d or nifedipine 30-80 mg/d ± ISDN 20-80 mg/d	21 (68%) of 31 patients were asymptomatic at last visit and 9 had improved symptoms
		Takahashi et al.³⁶ N = 1429	Nitroglycerin and isosorbide mono-/dinitrate (any dose)	Nitrate therapy did not improve the long-term prognosis (7% with nitrate vs 5% without, P = .17).
	Statins	Tani S et al.³⁷ N = 25	Bendipine 4 mg (titrated to a maximum dose of 12 mg daily) and pravastatin 10-20 mg a day (titrated to LDL < 100 mg/dL) for 6 months	12 (48%) of the 25 patients who initially tested positive for vasospastic angina subsequently tested negative. Among those who subsequently tested negative for vasospastic angina, a larger reduction in LDL and increase in HDL cholesterol was seen (−20% vs −7.8%, P = .07 and 26.8% vs 9.3%, P < .001, respectively)	Statins may be beneficial in reducing incidence of vasospastic angina. This appears to be related to LDL reduction and HDL increase. Furthermore, the addition of a statin to CCB therapy may further reduce the incidence of vasospastic angina.
	Statins	Yasue H et al.³⁸ N = 64	Fluvastatin 30 mg/d plus a CCB (extended release diltiazem 100-200 mg/d or extended release nifedipine 20-40 mg/d) or CCB alone	After 6 months of treatment in 64 patients with initial positive acetylcholine provocation, vasospastic angina was suppressed in 16 patients (51.5%) with statin and CCB therapy vs 7 patients (21.2%) with CCB monotherapy (P = .0231)
	Alpha₁-adrenergic receptor antagonists	Robertson et al.³⁹ N = 6	Prazosin 4 mg every 8 hours.	No significant differences in the number or length of ischemic episodes, difference in chest pain, or nitroglycerin use	The use of prazosin as monotherapy for the treatment of vasospastic angina does not significantly decrease the use of SL NTG, number or length of ischemic episodes, or ST-segment changes but is associated with more adverse effects. However, combination therapy with a CCB or LAN significantly decreases the frequency and intensity of angina symptoms.
		Tzivoni et al.⁴⁰ N = 6	Prazosin 8-30 mg daily, combined with low dose LAN or nifedipine IR	Ameliorated or markedly reduced frequency and intensity of angina symptoms
		Winniford et al.⁴¹ N = 6	Prazosin 9-15 mg per day compared to placebo	Compared to placebo, prazosin did not change the weekly number of chest pain episodes, nitroglycerin tablets used, or transient ST-segment deviations; prazosin contributed to more adverse effects, compared to placebo
Avoid	Beta blockers	Robertson et al⁴² N = 6	160 mg on day 1, followed by 640 mg/d × 2 days vs placebo	No significant differences found between number of episodes of vasospasm with either low or high dose propranolol. Average length of episode was longer with low- and high-dose propranolol compared to placebo (3.1 and 3.4 minutes, respectively vs 1.3 minutes; P < .005)	The use of β-blockers should be avoided in vasospastic angina as they appear to be ineffective and may exacerbate coronary vasospasm.
	Beta blockers	Antman et al.³² N = 127	No doses specified	19% of these patients found propranolol remotely effective for alleviating symptoms; 69% of patients found that propranolol was completely ineffective and 9.5% had an increased frequency of angina attacks associated with the use of the propranolol (no P values provided)
	ASA	Miwa K et al.⁴³ N = 4	High-dose ASA (4000 mg/d)	“The administration of [high-dose] aspirin increased the frequency of angina attacks markedly” (authors conclusions, no statistics provided)	Regardless of dose, ASA therapy fails to show benefit for reducing morbidity or recurrent angina attacks. High dose ASA may be associated with increased incidence of angina attacks
		Kim et al.⁴⁴ N = 424	Low-dose ASA (< 325 mg/d) vs no ASA	Diffuse coronary vasospasm provoked by ergonovine was more frequently observed in the non-ASA group (29.2% vs 43.7%, P = .002)
		Park JY et al.⁵ N = 2789	ASA < 100 mg vs no ASA	Investigators failed to find a difference in readmission due to recurrent angina (19.3% with ASA vs 19.0%% without, P = 1.000) Use of low-dose ASA was an independent risk factor for coronary vasospasm (adjusted OR 1.6; 95% CI, 1.0-2.3; P = .031)

Abbreviations: SL NTG, sublingual nitroglycerin; DHP, dihydropyridine; CCB, calcium channel blocker; ISDN, isosorbide dinitrate; LAN, long-acting nitrates; ASA, aspirin; NS, not significant; HDL, high-density cholesterol; LDL, low-density cholesterol; IR, immediate release.

^aAll P values are in comparison to placebo unless otherwise specified.

^bStatistical significance was found in favor of treatment groups unless otherwise specified.

Figure 1.

Medication management in vasospastic angina.

Calcium Channel Blockers

The different subclasses of CCBs include the dihydropyridines (DHP) and non-DHP (diltiazem and verapamil). Both subclasses have similar mechanisms of action in which they work on peripheral arteries to induce vasodilation and on the myocardium via inhibition of calcium influx through the L-type calcium channels in excitable membranes.⁴⁵ Dihydropyridine CCBs inhibit the entry of calcium intracellularly, specifically in the periphery, resulting in peripheral vasodilation.⁴⁶ Non-DHP CCBs have relatively more negative chronotropic and inotropic effects, thereby reducing cardiac workload by reducing left ventricular contractility and myocardial oxygen demand.⁴⁵ Verapamil and diltiazem undergo extensive first-pass metabolism as only 10% to 20% and 40%, respectively, of the orally administered dose reaches systemic circulation.⁴⁷ Thus, higher doses of non-DHP CCBs are recommended during initiation of therapy. This effect is not observed with DHPs.⁴⁷ Additionally, use of verapamil extended release (ER) at night has been shown to significantly improve symptom-limited exercise tolerance, angina episode duration, and heart rate in patients with ischemia, compared to amlodipine.^45,48 Many of the adverse events associated with DHP CCBs are caused by peripheral vasodilating properties, whereas negative chronotropic effects of non-DHP CCB cause bradycardia and atrioventricular conduction delay, including second- and third-degree atrioventricular block.⁴⁵ In general, short-acting DHP CCBs, such as nifedipine immediate release (IR), can worsen cardiac outcomes through induction of reflex sympathetic activation leading to an increase in cardiac oxygen demand, tachycardia, and increased myocardial ischemia.⁴⁹ The non-DHP CCBs’ ability to suppress sinoatrial activity is exaggerated in elderly individuals and in patients with chronic kidney disease due to a reduction in renal clearance of these agents.⁴⁵ Additionally, non-DHP CCBs can be harmful in patients with a history of heart failure with reduced ejection fraction due to worsening of heart failure from their negative inotropic effects.⁴⁶

It has been shown that verapamil IR and nifedipine IR have similar efficacy, but there are more adverse effects associated with nifedipine, including orthostatic hypotension, pedal edema, nausea, anorexia, and dizziness.⁵⁰ A reduction in ischemia on exercise treadmill tests, reduced ST-segment changes on ambulatory ECG monitoring, increased coronary artery blood flow, and improved ventricular dysfunction associated with ischemia were found with both agents.^51

–57 These results support the notion that CCBs are highly effective in reducing ischemic episodes in patients with vasospastic angina.^58
–60 However, there is little evidence showing that CCBs decrease the modulation of calcium sensitivity postulated by the increase in calcium sensitivity phenomenon.⁶¹ This may explain the presence of recurrent angina attacks even while on mainstay therapy.

Case reports from the 1970s demonstrated nifedipine’ s angina relieving effects in vasospastic angina.⁶² In 1980, Hill et al found that nifedipine ER 40 to 160 mg reduced weekly occurrences of angina from 16 to 2 episodes as well as nitroglycerin requirements in 127 patients with vasospastic angina. Complete angina relief and reduction in the frequency of angina was shown in over 50% of patients.³² In small retrospective studies, nifedipine IR was found to significantly reduce the number of anginal attacks in doses ranging from 30 to 120 mg in patients having vasospastic angina.^33,49,63

A randomized, multicenter, double-blind, withdrawal study compared nifedipine to placebo. This study began with a 2-week, single-blinded, phase-assessed tolerability of nifedipine. Next, 38 patients entered a 4-week randomization phase, which was prematurely stopped due to a significant increase in angina attack frequency in the placebo group, compared to the nifedipine group (37% vs 0.05%).³³

The efficacy and safety of amlodipine were studied in a randomized, single-blinded trial, where 52 patients with documented vasospastic angina received amlodipine 10 mg or placebo. Over the course of 4 weeks, daily anginal attacks were significantly decreased in the amlodipine arm compared to placebo. During the same time frame, the number of nitroglycerin (short-acting) tablets used daily was less in patients receiving amlodipine but failed to attain statistical significance. Twenty-nine patients were treated with amlodipine 5 to 15 mg over 1 year and demonstrated that anginal attacks decreased from 1.6 episodes daily to 0.1 episodes daily at 1 year. Furthermore, short-acting nitroglycerin use was decreased from 1.3 tablets per week to 0.2 tablets per week. Peripheral edema was the only adverse event more commonly observed, compared to placebo (5 vs 3 patients).⁵⁹

Small double-blinded, randomized, and crossover studies have evaluated the efficacy and safety of verapamil in vasospastic angina.^64,65 Verapamil was found to significantly decrease the frequency of angina attacks, administration of nitroglycerin tablets per week, number of hospitalizations, and number of transient ST-segment deviations with limited adverse effects.^64,65 Similarly, small prospective randomized, double-blinded crossover studies have investigated diltiazem.^66
–68 Results have shown a significant decrease in angina-free days, frequency of angina attacks, and nitroglycerin consumption when doses over 240 mg daily were used.^31,67,68

Patients with coronary artery spasm and minor coronary atherosclerosis or normal coronary arteries were examined by Freedman et al. After a mean follow-up of 21 months, 27 patients were treated with verapamil IR 120 to 600 mg daily (mean 314 mg/d). Four verapamil nonresponders received nifedipine IR 30 to 80 mg daily (mean 58 mg/d) and 16 patients were treated with isosorbide dinitrate 20 to 80 mg daily (mean 41 mg/d) in combination with either verapamil or nifedipine. The majority (67%) of patients were asymptomatic; 29% of patients had improvements in monthly anginal attacks. One patient experienced 8 episodes of angina per month. Six patients had stopped verapamil, however, 5 of these 6 patients remained asymptomatic for a mean of 10 months.⁶⁹

Currently, CCBs are recommended as first-line agents for treatment and prevention of vasospastic angina. According to the 2014 NSTE-ACS guidelines, treatment with either a non-DHP or DHP CCB alone or in combination with long-acting nitrates (LAN) is recommended in patients with vasospastic angina. Alternatively, some evidence has shown the benefit of using combined non-DHP and DHP CCBs therapy for the treatment of vasospastic angina.⁶⁵ A CCB in a moderate to high dose (eg, verapamil 240-480 mg daily, diltiazem 180-360 mg daily, or nifedipine ER 60-120 mg daily) is recommended for initiation in newly diagnosed vasospastic angina.^{30,58
–60,66}

Nitrates

Nitrates not only dilate the coronary vasculature but also reduce ventricular filling pressures through venodilation.⁶⁷ Through coronary vasodilation, nitrates may enhance subendocardial perfusion of ischemic areas in the ventricular myocardium.⁶⁷ However, the majority of the antianginal effect of nitrates stem from their ability to decrease myocardial oxygen demand through systemic venodilation.⁶⁷ For acute angina attacks, rapid-acting nitrate preparations are preferred due to their quick onset. Onset can be seen as soon as 1 minute following short-acting nitrate administration, such as with the use of intravenous or sublingual nitroglycerin.⁶⁸ The efficacy of LANs for the chronic treatment of vasospastic angina is well documented. Isosorbide dinitrate or isosorbide mononitrate ER have a longer onset of action compared to the sublingual nitroglycerin and can provide relief for a longer period of time. Long-acting nitrates have been proven to suppress acute angina attacks and may also help to prevent recurrent attacks.³⁵ In practice, CCBs are typically preferred over LAN, for vasospastic angina, due to potential nitrate tolerance. Repeat dosing of LAN leads to a waning effect known as tolerance or tachyphylaxis.⁷⁰ Although there are many proposed mechanisms for tachyphylaxis, the most plausible appears to be the formation of a superoxide (O₂ ⁻) molecule. Superoxide has multiple downstream receptor effects which ultimately leads to inhibition of soluble guanylate cyclase, the enzyme responsible for nitric oxide signaling. A nitrate-free interval of 12 to 14 hours between the evening dose and morning dose should be utilized to reduce the formation of superoxide and prevent nitrate tolerance.⁷⁰

The combination of a CCB with a nitrate may have a synergistic effect and provide relief when a patient has vasospastic angina refractory to monotherapy. In a prospective crossover trial by Conti et al, 19 patients were treated in the catheterization laboratory with a 1-time dose of sublingual nifedipine 10 mg and nitroglycerin 200 μg as an intracoronary infusion. The combination of nifedipine and nitroglycerin significantly dilated more coronary arteries compared to nifedipine alone.³⁵ No adverse reactions were noted. Although the addition of a nitrate to standard therapy may help alleviate symptoms, nitrates do not appear to have a long-term prognostic benefit.^34,71 In a study by Takahashi et al, 1429 patients with vasospastic angina were studied over a 32-month median follow-up period. The study included the use of conventional nitrates such as nitroglycerin and isosorbide mono-/dinitrate as well as nicorandil. Nicorandil, a vasodilator not available in the United States, is an adenosine triphosphate-sensitive potassium channel agonist with nitrate-like properties.⁷² A CCB was utilized in 90% of these patients. After a median follow-up period of 32 months, the use of nitrate therapy did not improve long-term prognosis.³⁶

Special considerations should be kept in mind when using nitrate therapy.⁷³ Common adverse effects associated with the use of nitrates include headache and flushing.⁷³ Tachycardia is also a common adverse effect; therefore, practitioners should consider addition of a non-DHP CCB, in order to decrease myocardial oxygen demand.⁷³ Due to the possibility for additive hypotension, nitrates are considered contraindicated within 24 hours of taking phosphodiesterase 5 (PDE₅) inhibitors, such as sildenafil or vardenafil, and within 48 hours of taking tadalafil.⁶⁹ Nitrates appear to be safe and effective for preventing or relieving acute angina attacks associated with vasospastic angina. However, the long-term prognostic benefit has yet to be elucidated. Therefore, nitrates should be used as second-line agents, when patients are not responding adequately to CCB therapy.

Aspirin

Limited data exist regarding the use of aspirin (ASA) in vasospastic angina without concomitant obstructive CAD.^5,43 Theoretically, high doses (> 325 mg daily) of ASA can aggravate coronary artery vasospasm by blocking production of prostacyclin via cyclooxygenase.^8,43 Low doses of ASA (< 100 mg) block thromboxane A₂, a vasoconstrictor implicated in coronary artery vasospasm, and therefore have a beneficial effect on the disease process.^8,43 However, clinical data are lacking. In a study by Kim et al, 424 patients were studied with a 1-year follow-up period. Diffuse vasospasm was more frequently observed in the non-ASA group (29% vs 44%). Investigators failed to find a difference in readmission due to recurrent angina between groups (19% vs 19%).⁴⁴ Park et al also studied the use of low-dose ASA (<100 mg) and its effect on vasospastic angina through the use of intracoronary acetylcholine provocation testing. In this study, 2789 patients were divided into 2 groups: those taking low-dose ASA (n = 221) and those who were not on ASA therapy (n = 2568). The use of low-dose ASA was associated with a higher incidence of ischemic symptoms and coronary vasospasm (adjusted odds ratio 1.6; 95% confidence interval, 1.0-2.3). However, significant differences in baseline demographics including age, diabetes mellitus, hypertension, and hyperlipidemia may have confounded these results.⁵ In general, high-dose ASA should be avoided in patients with vasospastic angina, as it may provoke exacerbations. Low-dose ASA appears to be safe and may be effective in preventing acute attacks; however, robust data are lacking.

Beta-Adrenergic Receptor Antagonists

The use of beta-adrenergic receptor blockers that do not possess alpha₁-adrenergic antagonist activity (ie, all beta-adrenergic receptor blockers except labetalol and carvedilol) should be avoided in vasospastic angina as they can exacerbate coronary vasospasm.^32,42,73 In a prospective cohort of 127 patients by Antman et al,³² a subset of patients with vasospastic angina were treated with propranolol. Only 19% of these patients found propranolol partially effective for alleviating symptoms, 69% of patients found that propranolol was completely ineffective, and 9.5% had an increased frequency of angina attacks associated with the use of the propranolol (no P values provided).The data surrounding the use of beta-adrenergic receptor antagonists are sparse; however, it would pharmacologically make sense to avoid these agents.³³ Beta₂-adrenergic receptor stimulation dilates peripheral blood vessels. Therefore, blockade of beta₂-adrenergic receptors may lead to unopposed alpha₁-adrenergic receptor stimulation, converting the effects of sympathetic stimulation into a more powerful alpha₁-adrenergic (vasoconstricting) response.^8,73,74 In general, beta-adrenergic receptor antagonists should be avoided in vasospastic angina due to their potential to exacerbate or provoke attacks. If a beta-adrenergic receptor antagonists is absolutely indicated, labetalol or carvedilol may be considered because these agents possess mixed (alpha₁- and beta-adrenergic receptor antagonist) properties, which may result in overall vasodilation.

HMG-CoA Reductase Inhibitors

HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme) reductase inhibitors, or “statins,” have been shown to be effective in preventing coronary artery vasospasm.^37,38 Beyond their ability to improve lipid metabolism, statins exert pleiotropic effects, such as antioxidant activity, which may help attenuate vasoconstriction.³⁸ Studies have shown when endothelial function and nitric oxide production are impaired in coronary arteries, vasospasm is exhibited.³⁸ Statins may help to improve endothelial function and thus mitigate vasoconstriction.³⁷ Yasue et al studied 64 patients with coronary vasospasm.³⁸ These patients were randomized to receive fluvastatin 30 mg daily plus a CCB (diltiazem ER 100-200 mg daily or nifedipine ER 20-40 mg daily) versus a CCB alone at the same dose. After 6 months of treatment, coronary vasospasm was significantly suppressed in 16 (52%) patients with statin and CCB combination therapy compared to 7 (21%) patients with CCB monotherapy. Although the use of a CCB significantly reduced the incidence of vasospasm, the addition of a statin appeared to be more effective.³⁸ Tani et al also showed positive results with statins. Twenty-five patients with coronary artery vasospasm (as confirmed by acetylcholine provocation test) were started on a CCB (bendipine 4 mg titrated to a maximum dose of 12 mg daily) and pravastatin (10-20 mg daily titrated to keep low-density lipoprotein cholesterol [LDL-C] levels < 100 mg/dL). After 6 months of therapy, 12 (48%) patients tested negative for coronary artery vasospasm. It was also found that those who tested negative for vasospasm had a larger reduction in LDL-C and a larger increase in high-density lipoprotein cholesterol (HDL-C) compared to those who continued to test positive (−20% vs −8% and 27% vs 9%, respectively).³⁷ Statins appear to be safe to use in vasospastic angina; however, larger scale, double-blind studies are needed in order to provide concrete recommendations. Therefore, statins should be considered a treatment option when more traditional therapies have been exhausted.

Alpha₁-Adrenergic Receptor Antagonists

The link between alpha-adrenergic receptors and their effects on coronary vasospasm has yet to be elucidated. Conflicting evidence exists regarding the clinical utility of using alpha₁-adrenergic receptor antagonists to treat vasospastic angina, which dates back to the early 1970s. Early experimental analysis of alpha₁-adrenergic receptor antagonist utility began with the administration of the alpha₁-adrenergic receptor antagonist phenoxybenzamine, which prevented the occurrence and spontaneous episodes of coronary vasospasm.⁷⁵ The antianginal effects of phenoxybenzamine were also evident in patients with exercise-induced vasospasm after administration of phenoxybenzamine. Another hypothesis exhibiting the influence of the alpha₁-adrenergic receptor on the etiopathophysiology of vasospastic angina is the negative effects of beta-adrenergic receptor blocker administration. Propranolol appeared to exacerbate angina symptoms due to the proposed mechanism of unopposed alpha₁-adrenergic receptor stimulation from catecholamines such as epinephrine.⁴² Additionally, there are data to suggest that postsynaptic alpha₂-adrenergic receptor activation may exacerbate variant angina syndrome.⁷⁵ Nevertheless, very little is known regarding the clinical utility of inhibiting alpha₂-adrenergic receptors peripherally as currently there are no available agents that inhibit peripheral alpha₂-adrenergic receptors.⁷⁶

The role of alpha-adrenergic receptors in vasospastic angina is not only unclear, but the quality of evidence available does not lend itself to support using alpha₁-adrenergic receptor antagonists to treat vasospastic angina. Clinically, the use of alpha₁-adrenergic receptor antagonists in the treatment of vasospastic angina is based on limited data and evidence. In a randomized, double-blind, placebo-controlled trial, 6 patients with vasospastic angina were given prazosin (alpha₁-adrenergic receptor antagonist) at a maximum dose of 4 mg every 8 hours. Despite increasing the amount of phenylephrine by greater than 6-fold (required to raise the systolic arterial pressure by 25 mm Hg), there were no significant differences in the number or length of ischemic episodes or difference in chest pain or nitroglycerin use.³⁹ In a study using 6 patients by Tzivoni et al, high doses of prazosin (8-30 mg daily) combined with low-dose LAN or nifedipine IR ameliorated or markedly reduced frequency and intensity of angina symptoms.⁴⁰ Nevertheless, in 1 patient, prazosin was discontinued due to hypotension and dizziness. Symptoms returned in 4 patients when the drug was discontinued, but once restarted, symptoms disappeared. While this study shows promising results, the results were only out of 6 patients and the follow-up period was 4 to 6 months, which may have been too short in terms of evaluating recurrence of vasospastic angina symptoms. Furthermore, many of the patients had a myocardial infarction, where the pathophysiology differs compared to vasospastic angina. Many patients were receiving nifedipine IR, which can exacerbate ischemic symptoms.⁴⁰ In a study by Winniford et al, 6 patients were enrolled in a double-blind, randomized, placebo, double-crossover trial for 4.5 months. Patients were given 9 to 15 mg of prazosin per day compared to placebo. Prazosin did not change the weekly number of chest pain episodes, nitroglycerin tablets used, or transient ST-segment deviations. Moreover, prazosin contributed to orthostatic hypotension and headache in 4 patients. While this study was over 4.5 months, there were only 6 patients enrolled in the trial and some patients had obstructive CAD.⁴¹

There may be a role for mixed alpha₁-and alpha₂-adrenergic receptor antagonism in the treatment of vasospastic angina based on evidence of possible alpha₂-adrenergic receptor influence.⁷⁷ Unfortunately, to date, only prazosin, a strictly alpha₁-adrenergic receptor antagonist, has been used in the treatment of vasospastic angina, and many of the studies previously mentioned only used prazosin as monotherapy. Perhaps the multiple postulated mechanisms of vasospastic angina may warrant multiple pharmacotherapeutic agents with differing mechanisms of action in order to provide more symptom relief. However, based on the available literature, when high doses of alpha₁-adrenergic receptor antagonists were used, adverse drug effects such as hypotension and headache precipitated. Currently, the 2014 NSTE-ACS guidelines do not provide a specific class recommendation with respect to alpha₁-adrenergic receptor antagonist use. Rather, it is stated that “alpha blocker use may be effective and can be added.”^30(p85) Based on the available literature, the most appropriate recommendation is to add alpha₁-adrenergic receptor antagonist to a regimen when pharmacotherapy, such as high dose non-DHP CCBs in combination with LAN, does not ameliorate symptoms. Patients should take the first dose of an alpha₁-adrenergic receptor antagonist at bedtime to decrease the sensation of the first-dose effect that is precipitated by alpha₁-adrenergic receptor antagonists in patients who are naive to this drug class.⁷⁸ Additionally, patients should be monitored cautiously for adverse effects, such as central nervous system depression or hypotension and tachycardia, both of which may exacerbate ischemic symptoms.⁷⁸

Alternative Pharmacotherapy

Review of vasospastic angina treatment reveals tenuous pharmacotherapeutic treatment options. The utility of alternative pharmacotherapy to treat vasospastic angina in patients who may be refractory to therapy previously mentioned (or present with intolerances or contraindications) is equally scant in terms of clinical experience. Moreover, the literature surrounding alternative pharmacotherapy is based on a single trial or case reports. The late sodium ion channel inhibitor, ranolazine, is indicated for the treatment of chronic stable angina.⁷⁹ While a wealth of data exist on the use of this agent in stable CAD, there is limited evidence in its use for vasospastic angina. In a pilot study, which included only women with angina and evidence of myocardial ischemia without obstructive CAD, patients were randomized to either ranolazine titrated to 1000 mg twice daily or placebo for 4 weeks, separated by a 2-week washout period. Most patients enrolled in the trial were on beta-adrenergic receptor antagonists, angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers, and statin therapy. Some patients also received CCBs and LAN. Results of the trial showed that compared to placebo, ranolazine improved physical functioning, angina stability, and quality of life. Nevertheless, this study was comprised of only 20 patients, all of whom were women. Notably, if a clinician were to consider this approach, ranolazine should be added as background therapy in patients who have failed combination therapy with a beta-adrenergic receptor antagonist, CCB, and/or a LAN. Clinicians should also be mindful of using ranolazine in patients who are concomitantly taking other medications, as ranolazine is a major substrate of CYP P450 substrate, isoenzyme 3A4, and p-glycoprotein, which may cause the patient to be more susceptible to drug–drug interactions.⁷⁹ Additionally, ranolazine should be used with caution in patients with renal or hepatic disease, those with or are at risk of QTc interval prolongation, and those with a history of malignancy.⁷⁹ Ranolazine is contraindicated in patients with hepatic cirrhosis (of any degree) and with concurrent use of strong CYP3A4 inducers or inhibitors.⁷⁹

A more novel pharmacological approach to treating vasospastic angina has recently emerged. Endothelin 1 (ET-1) is a potent vasoconstrictor and increased levels have been linked to coronary vasospasm. Endothelin 1 receptors have 2 subtypes, A and B. Stimulation of ET-1 subtype A receptors in smooth muscle results in vasoconstriction. Stimulation of subtype B receptors that are present in endothelial and vascular smooth muscle have both vasoconstrictive and dilatory effects.⁸⁰ In a case report by Krishnan et al, the nonselective endothelin receptor antagonist, bosentan, was used in a patient with vasospastic angina. At a dose of 125 mg twice daily, bosentan successfully reversed angina that was refractory to maximum tolerated doses of diltiazem and isosorbide mononitrate, along with supplementary doxazosin and nicorandil. Subsequent inadvertent withdrawal of the medication led to recurrence of symptoms, which again resolved with readministration of the agent.⁸¹ While bosentan may prove promising with more robust experimental designs, endothelin receptor antagonists do not come without risk. Bosentan is under strict regulation through Risk Evaluation and Mitigation Strategy (REMS) program, in which prescribers, patients, and pharmacies must enroll to use this medication. This is because of adverse effects such as hepatotoxicity, teratogenicity, peripheral edema, and hematologic changes. Moreover, bosentan is not available generically in the United States, and cost may limit the patient’s access to this agent. Based on the available evidence and the amount and severity of adverse effects, use of bosentan to treat vasospastic angina should be approached cautiously and perhaps used as last-line therapy to control angina that is refractory to all conventional and nonconventional therapies.

Most recently, the Study to evaluaTe the Efficacy and safety of Pletaal (ciLostazoL) (STELLA) trial, a randomized, multicenter, double-blind, placebo-controlled trial evaluated the safety and efficacy of cilostazol in patients with vasospastic angina. Cilostazol is a selective inhibitor of phosphodiesterase-3. Inhibition of phosphodiesterase-3 produces vasodilation, antiplatelet activity, improved blood flow, and inhibition of vascular smooth muscle cell growth.⁸² While cilostazol is indicated for the treatment of intermittent claudication in peripheral artery disease, its potential for the treatment of vasospastic angina has only been explored recently. In the STELLA trial, patients with vasospastic angina were studied in multiple hospitals throughout South Korea and were randomized to either amlodipine 5 mg daily plus cilostazol titrated to 100 mg twice daily or amlodipine plus placebo. The primary end point was reduction in weekly incidence of chest pain, which was greater in the cilostazol group compared to placebo. While it did not reach statistical significance, more patients in the cilostazol group experienced headache, paresthesia, peripheral edema, and gastrointestinal symptoms (known adverse effects of cilostazol). Notably, there were only 49 patients who were enrolled, and this trial was mostly comprised of males. Another important limitation is that the duration of the trial was only 4 weeks, which may not be sufficient in assessing the long-term safety and efficacy of cilostazol in the treatment of vasospastic angina.⁸³ Based on the results of this study, cilostazol may be appropriate as add-on therapy in patients who fail conventional therapy with CCBs. However, there are safety concerns when using cilostazol in patients with cardiovascular disease (heart failure and CAD), renal or hepatic dysfunction, thrombocytopenia, and active pathological bleeding.⁸² Cilostazol should also be discontinued approximately 4 days prior to surgery.⁸² Common adverse effects of cilostazol include headache, diarrhea, palpitations, and dizziness.⁸² Additionally, as cilostazol is a major substrate of isoenzymes CYP 3A4 and 2C19 clinicians should be mindful of drug–drug interactions when using cilostazol concomitantly with other agents.⁸²

Summary

While the incidence of mortality associated with vasospastic angina is low, patients do experience a significant morbidity burden. Hospitalizations are costly and associated with a decreased quality of life, which underscores the importance of treating patients with the appropriate pharmacotherapy in vasospastic angina. Due to the vague nature of the pathophysiology and etiology of vasospastic angina, targeting a specific disease process is not possible, therefore the choice of pharmacotherapy should be based on patient specific factors. Calcium channel blockers should be considered first-line therapy, especially in patients who have comorbidities such as atrial fibrillation, hypertension, or heart failure with preserved ejection fraction. Calcium channel blockers should be used with caution in patients with heart failure with reduced ejection fraction, hypotension, conduction abnormalities, and hepatic dysfunction. Calcium channel blockers should also be used with caution when concomitantly administered with other medications, as drug–drug interactions are possible. Long-acting nitrates can ameliorate ST-segment changes as well as symptoms of vasospastic angina. Long-acting nitrates can be added on to CCB therapy, but caution should be used especially when concomitantly used with a short-acting DHP as nitrates can synergistically cause reflex tachycardia, hypotension, flushing, and headache. The clinical utility of adding alpha₁-adrenergic receptor antagonists to conventional therapy (LAN/CCB) is still unclear. If patients are still experiencing symptoms with a CCB plus a LAN, an alpha₁-adrenergic receptor antagonist may be considered. However, adverse effects such as hypotension, reflex tachycardia, and central nervous system depression are common in patients receiving alpha₁-adrenergic receptor antagonists. The clinical utility of ASA and statins has yet to be elucidated. Aspirin and statins should be used in patients who carry a clear indication for use of these agents, respectively. Beta-adrenergic receptor antagonists (especially agents lacking alpha₁-adrenergic receptor antagonism) should be used with caution in patients with vasospastic angina, as administration may cause unopposed alpha₁-adrenergic receptor stimulation, which could exacerbate angina symptoms. Investigation into alternative pharmacotherapy is under way and includes agents such as bosentan, cilostazol, and ranolazine.^81,83,84 Evidence regarding the use of these agents comes from case reports and should be applied to the clinician’s patient population with caution, and these patients should be diligently monitored. No matter the strategy chosen, the use of pharmacotherapy for the treatment of vasospastic angina should be patient-specific and guided by patient-specific factors such as tolerability, adverse effects, drug–drug, and drug–disease interactions. The patient’s response in terms of safety and efficacy during the treatment of vasospastic angina should be evaluated frequently so that morbidity can be prevented. Patients should also be educated to contact emergency medical services in the event that nitroglycerin does not ameliorate symptoms, as symptoms of vasospastic angina can overlap with those of a myocardial infarction.

Footnotes

Acknowledgments

The authors would like to acknowledge the reviewers for ensuring the quality of this review.

Author Contributions

Harris, Justin R contributed to conception and design; contributed to acquisition, analysis, and interpretation; drafted the manuscript; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Hale, Genevieve M contributed to conception and design; contributed to acquisition, analysis, and interpretation; drafted the manuscript; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Dasari, Tarun W contributed to design; contributed to acquisition, analysis, and interpretation; drafted the manuscript; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Schwier, Nicholas C contributed to conception and design; contributed to acquisition, analysis, and interpretation; drafted the manuscript; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC Cardiovasc Imaging. 2011;4(5):514–522.

Pharmacotherapy of Vasospastic Angina

Abstract

Keywords

Introduction

Pathophysiology

Diagnosis

Risk Factors and Etiology

Pharmacotherapy of Vasospastic Angina

Calcium Channel Blockers

Nitrates

Aspirin

Beta-Adrenergic Receptor Antagonists

HMG-CoA Reductase Inhibitors

Alpha1-Adrenergic Receptor Antagonists

Alternative Pharmacotherapy

Summary

Footnotes

Acknowledgments

Author Contributions

Declaration of Conflicting Interests

Funding

References

Alpha₁-Adrenergic Receptor Antagonists