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Nitrates in the management of chronic coronary

syndrome
Authors: Joseph P Kannam, MD, Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC
Section Editor: Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA
Deputy Editor: Todd F Dardas, MD, MS

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2022. | This topic last updated: Mar 31, 2021.

INTRODUCTION

Nitroglycerin was the first medication used in 1879 by William Murrell for the treatment of
angina pectoris [1] and, in its extended release forms, still remains first-line drug therapy for
many patients [2,3].

While they act as venodilators, coronary vasodilators, and modest arteriolar dilators, the
primary antiischemic effect of nitrates is to decrease myocardial oxygen demand by producing
systemic vasodilation more than coronary vasodilation. This systemic vasodilation reduces left
ventricular systolic wall stress.

In patients with exertional stable angina, nitrates improve exercise tolerance, time to onset of
angina, and ST-segment depression during exercise testing. In combination with beta blockers
or calcium channel blockers, nitrates produce greater antianginal and antiischemic effects. (See
"Angina pectoris: Chest pain caused by fixed epicardial coronary artery obstruction" and
"Chronic coronary syndrome: Overview of care".)

Its use, however, is complicated by the development of tolerance with continuous therapy. (See
'Nitrate tolerance' below.)

MECHANISM OF ACTION
Nitrates dilate veins, arteries, and coronary arteries by relaxing vascular smooth muscle [4].
They produce these effects by entering vascular smooth muscle cells where they are
metabolized to 1,2-glyceryl dinitrate and nitrite, via mitochondrial aldehyde dehydrogenase-2
(ALDH2 or mtALDH), and then nitric oxide and S-nitrosothiols ( figure 1) [5]. Sulfhydryl groups
on ALDH2 are required for activity, which can explain the known sulfhydryl requirement for
vascular smooth muscle relaxation by nitrates [5].

Most of the antiischemic efficacy of nitrates pertains to their ability to decrease myocardial
oxygen demand as a result of systemic vasodilatation rather than any activity as a coronary
vasodilator. Nitrates do not have a direct effect on cardiac chronotropy or inotropy.

Effect on systemic hemodynamics — The nitrates are primarily venodilators due to increased

bioavailability to venous smooth muscle cells. Venodilation lowers preload (left ventricular end-
diastolic pressure) and therefore reduces wall stress, resulting in a decrease in myocardial
oxygen demand. The fall in preload is more pronounced with sitting or standing.

At low doses, nitrates cause a lesser degree of arterial and arteriolar dilatation, leading to little
or no change in systemic vascular resistance or blood pressure [4]. As the dose is increased, the
blood pressure falls, often accompanied by reflex tachycardia. Wall stress is reduced at the
lower blood pressure, resulting in a further decrease in myocardial oxygen demand.

Some patients, especially those with hypovolemia, are extremely sensitive to the arteriolar
effect of nitrates and develop a profound drop in blood pressure which can aggravate
myocardial ischemia. In addition, arteriolar dilatation of the face can cause flushing and
meningeal arterial dilatation can cause headache, two common side effects of these drugs.

Problems can also occur with excessive venodilation. This can result in a marked decrease in
venous return, which induces cardiac emptying that triggers mechanical receptors in the heart,
possibly leading to hypotension and bradycardia consistent with the Bezold-Jarisch reflex
(vasovagal response) [6]. (See "Reflex syncope in adults and adolescents: Clinical presentation
and diagnostic evaluation".)

Effect on coronary hemodynamics — A nitrate-induced increase in coronary blood flow has

been proposed as a potential mechanism for relieving ischemia. Animal and human studies
have shown that nitrates dilate both normal and abnormal coronary arteries [7]; this response
is preserved in saphenous vein grafts [8]. The clinical importance of this effect is uncertain
because the coronary arterioles in patients with a flow-limiting coronary stenosis are already
dilated to maintain resting blood flow, making further coronary dilation during ischemia
difficult.
There are, however, settings in which a direct effect on coronary hemodynamics may be
beneficial. Nitrates can reduce or reverse coronary vasospasm [9]. Thus, patients with primarily
vasospastic angina or a large vasoconstrictor component to their angina can benefit from the
direct coronary action of nitrate therapy. Nitrates also indirectly improve subendocardial blood
flow as the reduction in left ventricular end-diastolic pressure induced by systemic venous
dilatation decreases the resistance to coronary blood flow from epicardium to endocardium
[10]. In addition, nitrates may lower the resistance to collateral vessel blood flow [11].

Antiplatelet and antithrombotic properties — Nitrates have significant antiplatelet and

antithrombotic properties; however the clinical importance of these potentially beneficial
effects is unclear [12]. Stimulation of platelet guanylate cyclase by nitrates prevents fibrinogen
binding to platelet IIb/IIIa receptors, which is essential for platelet aggregation [13].
Transdermal nitroglycerin has been shown to inhibit platelet aggregation and thrombus
formation in patients with angina [14].

USE

Nitrates, usually in the form of a sublingual preparation, are the first-line therapy for the
treatment of acute anginal symptoms. Patients should be instructed to use them at the onset
of angina.

A sublingual nitroglycerin tablet may be recommended for the prophylaxis of anginal episodes
and we often recommend them in patients with predictable and stable angina. For example,
patients who have undergone incomplete revascularization who get angina at a predictable
workload may be good candidates for prophylactic nitroglycerin. Some patients may benefit
from a repeat dose if angina occurs during the activity.

Long-acting nitrates are added to beta blockers (with or without calcium channel blockers) to
control stable angina. In patients with exertional stable angina, chronic nitrate therapy using
oral or dermal preparations improves exercise tolerance, time to onset of angina, and ST-
segment depression during exercise testing. In combination with beta blockers or calcium
channel blockers, nitrates produce greater antianginal and antiischemic effects compared with
those drugs without nitrates. However, the long-term utility of nitrates is limited by the
induction of nitrate tolerance.

NITRATE TOLERANCE
Tolerance has been a major problem with the use of nitrates as chronic antianginal therapy. It
was first observed in individuals exposed to nitroglycerin during the production of explosives.
These workers developed severe headache and dizziness after the initial exposure. These side
effects would then diminish after several days. If, however, exposure was avoided for several
days, the symptoms would return after reexposure.

A similar sequence occurs in humans as chronic nitrate therapy for angina pectoris is associated
with attenuation and at times abolition of the hemodynamic and antianginal effects.

Mechanisms of tolerance — How nitrate tolerance occurs is incompletely understood. It is due

to attenuation of the vascular effect of nitrates, not to altered pharmacokinetics [2].

At least three, not mutually exclusive, mechanisms have been proposed to explain the
development of nitrate tolerance [2]. These include:

● Impaired nitroglycerin bioconversion to 1,2-glyceryl dinitrate with decreased formation of

nitric oxide. This effect is nitrate-specific and is not seen with non-nitrate sources of nitric
oxide such as nitroprusside [15]. Consistent with this theory are the experimental
observations that there is no tolerance to the effect of S-nitrosothiols and that the activity
of mitochondrial aldehyde dehydrogenase-2 (mtALDH), the enzyme required for
metabolism of nitrates to 1,2-glyceryl dinitrate in markedly reduced [5]. The same findings
can be induced by inhibitors of mtALDH [5].

● Reduced bioactivity of nitric oxide [16]. Consistent with this theory is the finding in an
animal study that vascular and hemodynamic tolerance to nitrates occurred despite high
levels of nitric oxide and rates of nitric oxide formation that were similar in those animals
that were not tolerant [17]. Also in support of this hypothesis is that transgenic animals
that overexpress endothelial nitric oxide synthase have chronically elevated nitric oxide
release, which is associated with reduced vascular reactivity to nitric oxide-mediated
vasodilators [18].

● Activation of the vasoconstrictor renin-angiotensin-aldosterone and sympathetic nervous

systems in response to nitrate-induced vasodilation [19,20]. There is also increased
peripheral sensitivity to these vasoconstrictors, an effect that can be reversed by
angiotensin converting enzyme inhibition [19]. Abnormal coronary vasoconstrictor
responses have also been described with continuous nitrate exposure [21].

Prevention — Several strategies have been attempted to prevent nitrate tolerance, the most
effective being intermittent therapy with an adequate nitrate-free interval (around 8 to 10
hours). It is thought that a nitrate-free interval permits the regeneration of reduced sulfhydryl
groups, thereby restoring vascular responsiveness to nitrates. Chronic therapy with N-
acetylcysteine, a sulfhydryl donor, does not appear to be effective in patients with stable angina
[22], in contrast to its acute benefit with intravenous nitroglycerin in those with unstable
angina. (See "Nitrates in the management of acute coronary syndrome".)

There are, however, two concerns regarding intermittent therapy:

● A time-zero effect, which refers to a deterioration in exercise performance relative to

placebo prior to the morning dose of nitrates.

● Rebound angina, which refers to an increase in angina during the nitrate-free interval.
There may result from a supersensitivity of the vessel wall to vasoconstrictors [23] or an
increased vasomotor response to acetylcholine, suggesting the development of
endothelial dysfunction [24].

Whether these effects occur to a clinically significant degree remains unclear [25-28]. Their
importance with the different nitrate preparations will be discussed below.

Several other methods have been proposed to reduce nitrate tolerance, although none is as yet
used clinically:

● Folic acid can reverse endothelial dysfunction, possibly by restoring the bioavailability of
tetrahydrobiopterin, a cofactor for nitric oxide synthase and/or arginine, its substrate. This
suggests a possible role for folic acid in preventing nitrate tolerance. This was examined in
a study of 18 subjects who were randomly assigned to folic acid (10 mg/day) or placebo
for one week; all patients received continuous transdermal nitroglycerin (0.6 mg/hour)
[29]. Compared to placebo, folic acid prevented the development of both endothelial
dysfunction and nitrate tolerance.

● Treatment for five to 10 days with L-arginine, the substrate for nitric oxide synthesis, can
modify or prevent the development of nitrate tolerance during continuous transdermal
nitroglycerin use [30].

● Hydralazine may attenuate nitrate tolerance, perhaps by preventing superoxide

generation [31]. This relationship could contribute to the efficacy of combined nitrate-
hydralazine therapy in patients with heart failure. (See "Overview of the management of
heart failure with reduced ejection fraction in adults".) In patients with angina pectoris,
hydralazine should be given in combination with a beta blocker because of the reflex
sympathetic activation.
 ● Other antioxidants may be helpful, at least from a theoretical perspective, such as vitamin
E [32] and vitamin C [33,34]. In addition, carvedilol, a beta and alpha blocker that also has
antioxidant activity, may prevent nitrate tolerance [35]. The importance of antioxidant
activity was suggested by a second report which compared carvedilol with another beta
and alpha blocker (arotinolol) that was devoid of antioxidant properties; only carvedilol
prevented nitrate tolerance [36].

Other drugs have had variable or no effect. These include angiotensin converting enzyme
inhibitors [19,37-39], and diuretics, which may have some antianginal activity by reducing the
plasma volume [39,40].

COMMONLY USED NITRATE PREPARATIONS

Numerous nitrate preparations are commercially available, including sublingual, buccal, oral,
spray, ointment, and transdermal preparations.

Sublingual nitroglycerin — Sublingual nitroglycerin remains the therapy of choice for acute

anginal episodes and prophylactically for activities known to elicit angina such as mowing the
lawn, playing tennis, or walking in cold weather. Our impression is that the prophylactic use of
nitroglycerin is not sufficiently emphasized to patients.

The onset of action is within two to five minutes and the duration of action is 15 to 30 minutes.
Tolerance is not a problem with sublingual nitroglycerin because of its intermittent
administration, even in patients on chronic nitrate therapy [41].

The recommended nitroglycerin dose is 0.3 mg (1/200 grains) to 0.4 mg (1/150 grains).

The traditional recommendation is for patients to take one nitroglycerin dose sublingually every
five minutes for up to three doses before calling for emergency medical services (EMS)
evaluation. However, studies suggest that this approach may result in significant delays in
obtaining EMS assistance [42,43]. For patients known to their providers to have frequent
angina, physicians may consider a selected, more tailored message that takes into account the
frequency and character of the patient's angina and their typical time course of response to
nitroglycerin.

If the sublingual nitroglycerin is potent, a slight tingling sensation should be felt under the
tongue. Tablets that crumble easily should not be used. The sublingual mucosa should be moist
for adequate dissolution and absorption of the tablet. A drink of water in patients with dry
sublingual mucosa prior to ingestion of the tablet may be necessary [44].
Nitroglycerin tablets are both heat and light sensitive. They should therefore be stored in a
tightly capped dark bottle in the refrigerator with only a small supply being carried by the
patient. Nitroglycerin tablets in an opened bottle should be discarded after 12 months.

Patient education is extremely important for the proper use of sublingual nitroglycerin. A
survey of 50 patients revealed a surprising lack of knowledge concerning the administration,
storage, and side effects of this preparation [45]. Only 12 percent knew the maximum dose in a
15 minute period, 28 percent knew the proper storage conditions for sublingual tablets, and 52
percent knew the most common side effects. It is important for health care providers, when
reviewing the medication list of coronary artery disease patients, to ensure that patients have
an active prescription for nitroglycerin.

Nitroglycerin spray — A less popular but equally effective means of administering sublingual
nitroglycerin is by metered dose spray. The spray dispenses of 0.4 mg of nitroglycerin. One to
two sprays can be used at the start of an attack and up to three sprays can be used in a 15
minute period. It has a shelf life of two to three years [46].

Isosorbide dinitrate — Isosorbide dinitrate (ISDN) is uncommonly used in practice. It has an

onset of action within 15 to 30 minutes and the duration of action is three to six hours. Low
bioavailability from hepatic metabolism has necessitated relatively large doses of 10 to 40 mg
three times daily.

The beneficial effects of a single dose of ISDN (15, 30, 60, 120 mg) were demonstrated in 12
patients with chronic stable angina [41]. There was a dose-related reduction in systolic blood
pressure that persisted for eight hours. Exercise duration improved up to eight hours after the
15 and 30 mg dose; there was no added benefit with the 60 and 120 mg doses ( figure 2).

Unfortunately, tolerance has limited the usefulness of ISDN as a chronic antianginal agent. In
the study above, ISDN was given four times daily for two weeks [47]: both the blood pressure
and exercise responses were attenuated ( figure 2). In particular, exercise duration was only
increased for two hours after a dose and doses above 15 mg four times daily produced no
added benefit. The development of tolerance occurred despite higher plasma concentrations of
ISDN during maintenance therapy.

Several studies have altered the drug regimen in an attempt to prevent the development of
tolerance. One study, for example, examined the effect of 30 mg of ISDN given two (7 AM and
12 PM), three (7 AM, 12 PM, and 5 PM), and four (7 AM, 12 PM, 5 PM, and 11 PM) times daily for
one week [48]. Exercise duration until the onset of angina was assessed before and one, three,
and five hours after the morning dose. After a single initial dose, exercise duration significantly
increased versus placebo over the five hour observation period. After one week of therapy, two
and three (but not four) times daily dosing was associated with improved exercise tolerance
compared placebo; however, the benefit was less pronounced late in the day, indicating partial
tolerance. One limitation to the clinical utility of these results is that the response was
measured only to the morning dose of ISDN.

Another report questioned the antianginal efficacy of three times daily ISDN [49]. Eight patients
with chronic stable angina were given ISDN at 8 AM, 1 PM, and 6 PM. Exercise time increased
for at most three hours after the morning and afternoon dose but not substantially after the
evening dose ( figure 3). It was concluded that ISDN given three times daily offered
antianginal protection for at most six hours.

Isosorbide mononitrate — Extended release isosorbide mononitrate is the commonly used

oral nitrate. The dosage and side effects of the mononitrates are similar to those of isosorbide
dinitrate.

Nitrate tolerance is a potential problem. The extended release preparation when given once
daily in doses of either 120 and 240 mg [50].

Transdermal nitroglycerin — Transdermal nitroglycerin patches obtained United States Food

and Drug Administration approval in 1981 and gained wide acceptance for its convenience.
They are rarely used by our contributors.

Pentaerithrityl tetranitrate — Pentaerithrityl tetranitrate is a long-acting nitrate vasodilator

that has been used in patients with angina, in part because some studies have shown that it did
not induce nitrate tolerance [51]. In the CLEOPATRA study, 655 patients with chronic stable
angina were randomly assigned to pentaerithrityl tetranitrate (80 mg twice) daily or placebo
[52]. After 12 weeks, there was no difference in the primary end point of total exercise duration.

ADVERSE EFFECTS

Headache and flushing are common symptoms in patients taking nitrate therapy, and
hypotension can occur.

Contraindications — Nitrates are contraindicated in the following settings:

● In patients who have taken sildenafil or vardenafil within 24 hours or tadalafil within 48
hours (because of the risk of severe hypotension). (See "Sexual activity in patients with
cardiovascular disease".)
 ● In patients with hypertrophic cardiomyopathy in whom nitrates can induce or increase
outflow tract obstruction, even in those not known to have a resting gradient. (See
"Hypertrophic cardiomyopathy: Medical management for non-heart failure symptoms".)

● In patients with suspected right ventricular infarction, nitrates should be avoided, if

possible, because of the increased risk of inducing hypotension. (See "Right ventricular
myocardial infarction".)

In addition, nitrates should be used cautiously in patients with severe aortic stenosis or volume
depletion.

Our recommendations for the use of nitrates are generally consistent with those of guideline
organizations.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Chronic coronary
syndrome".)

SUMMARY AND RECOMMENDATIONS

● Nitrates – Sublingual nitroglycerin remains the treatment of choice for an acute anginal
attack or for prophylaxis prior to activities known to exacerbate angina. Chronic nitrate
therapy is used to prevent recurrent anginal episodes but must be dosed correctly in order
to prevent tolerance. Allowing for a sufficient nitrate-free interval, nitrates may be given
during the day or at night depending upon the patient's symptom complex:

• In patients with primarily exertional angina, nitrates are given during the day when the
patient is more active.

• In patients with nocturnal angina or heart failure, therapy at night may be more
beneficial.

Nitrates are especially useful in patients with heart failure, particularly at night in those
with significant orthopnea or paroxysmal nocturnal dyspnea. In addition, patients with
exertional dyspnea may benefit if nitrates are taken prior to exertion.
There is no difference in efficacy among isosorbide dinitrate and transdermal
nitroglycerin. Because of the problems with tolerance and rebound angina in the nitrate-
free interval, we usually reserve chronic nitrate therapy for second line antianginal
therapy. What follows are our recommendations for administering the most commonly
used nitrate preparations. The use of nitrates in specific clinical settings is discussed
separately.

• Sublingual nitroglycerin – Sublingual nitroglycerin remains the therapy of choice for

acute anginal episodes and prophylactically for activities known to elicit angina such as
mowing the lawn, playing tennis, or walking in cold weather. Our impression is that the
prophylactic use of nitroglycerin is not sufficiently emphasized to patients.

We give all patients with stable angina a prescription for sublingual nitroglycerin
(tablets or spray, depending upon patient preference). Patient education concerning
proper dosing, storage, and side effects of sublingual nitroglycerin is extremely
important. (See 'Sublingual nitroglycerin' above.)

• Isosorbide dinitrate – Proper dosing with isosorbide dinitrate is essential to prevent

tolerance. We recommend a dosing schedule of 8 AM, 1 PM, and 6 PM, which results in
a 14 hour nitrate dose-free interval. We begin with a dose of 10 mg three times daily,
and advance to 40 mg three times daily as needed. Alternatively, isosorbide dinitrate
can be taken twice daily at 8 AM and 4 PM. For this reason, we rarely use this
preparation; we prefer the sustained-release once-a-day preparation (see below) since
it can be given once daily.

• Isosorbide mononitrate – Some of our experts prefer isosorbide mononitrate to

dinitrate. When chosen, we prefer the sustained release preparation given its ease of
use. (See 'Isosorbide mononitrate' above.)

• Transdermal nitroglycerin – Nitroglycerin can be given transdermally in the form of a

patch. The patient must remember to remove the patch for 12 to 14 hours. If the
patient has angina with activity, we suggest that the patch be applied at 8 AM and
removed at 8 PM. If the patient has significant nocturnal angina, the patch can be worn
from 8 PM to 8 AM. We begin with a dose of 0.2 mg/hour; the dose can be increased to
0.8 mg/hour as needed. Since it can be difficult to remember to remove the patch after
12 hours, we do not use this option often, preferring the once-daily sustained-release
isosorbide mononitrate.

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47. Thadani U, Fung HL, Darke AC, Parker JO. Oral isosorbide dinitrate in angina pectoris:
comparison of duration of action an dose-response relation during acute and sustained
therapy. Am J Cardiol 1982; 49:411.
48. Parker JO, Farrell B, Lahey KA, Moe G. Effect of intervals between doses on the
development of tolerance to isosorbide dinitrate. N Engl J Med 1987; 316:1440.
49. Bassan MM. The daylong pattern of the antianginal effect of long-term three times daily
administered isosorbide dinitrate. J Am Coll Cardiol 1990; 16:936.

50. Chrysant SG, Glasser SP, Bittar N, et al. Efficacy and safety of extended-release isosorbide
mononitrate for stable effort angina pectoris. Am J Cardiol 1993; 72:1249.
51. Münzel T, Daiber A, Gori T. Nitrate therapy: new aspects concerning molecular action and
tolerance. Circulation 2011; 123:2132.

52. Münzel T, Meinertz T, Tebbe U, et al. Efficacy of the long-acting nitro vasodilator
pentaerithrityl tetranitrate in patients with chronic stable angina pectoris receiving anti-
anginal background therapy with beta-blockers: a 12-week, randomized, double-blind,
placebo-controlled trial. Eur Heart J 2014; 35:895.
Topic 1549 Version 20.0
GRAPHICS

Nitrate-induced vasodilation

Schematic representation of the mechanism by which nitroprusside

and nitrates induce vasorelaxation via the formation of nitric oxide and
subsequent activation of guanylate cyclase and generation of cyclic
guanosine monophosphate (cGMP).

Graphic 50622 Version 1.0

Tolerance to sustained isosorbide dinitrate

Duration of action of single oral doses of ISDN or placebo during acute and
sustained therapy in 12 patients with stable angina. Compared to placebo,
ISDN was associated with an increase in exercise time to angina that
persisted for eight hours during acute therapy but was attenuated in degree
and lasted for only two hours during sustained therapy. The improvement
was dose-dependent up to the 30 mg dose; there was no further
improvement with the 60 mg (not shown) and 120 mg doses.

Data from Thadani U, Fung H, Darke AC, Parker JO. Am J Cardiol 1982; 49:411.

Graphic 61032 Version 2.0

Limited efficacy of three times daily isordil
dinitrate

Mean duration of exercise time to angina at different hours during

days on which eight men with stable angina were given isosorbide
dinitrate (ISDN) or placebo at 8 AM, 1 PM, and 6 PM (arrows). A
signficant increase in exercise duration occurred after each dose of
ISDN; however, the total duration of benefit was only about six
hours.

Data from Bassan MM. J Am Coll Cardiol 1990; 16:936.

Graphic 79122 Version 2.0

Contributor Disclosures
Joseph P Kannam, MD No relevant financial relationship(s) with ineligible companies to
disclose. Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC Consultant/Advisory Boards: Bain Institute [CRO
for trials involving Edwards percutaneous valve devices];Cardiovascular Research Foundation [Data safety
monitoring board (RELIEVE-HF Trial)];Caristo Diagnostics Limited [Imaging and
inflammation/atherosclerosis];Icahn School of Medicine at Mount Sinai [Data safety monitoring board
(ENVISAGE-TAVI study)];Janssen Scientific Affairs [Executive committee (ORBIT Registries), chairman (Data
safety monitoring board), steering committee & writing committee (REVEAL Trial)];Kowa Research Institute
[Data safety monitoring board (PROMINENT study)];Medtronic[REVEAL AF study];MyoKardia[General
consulting];Philips Image Guided Therapy Corporation [Imaging];Sirtex Med Limited [General
consulting];Thrombosis Research Institute [Data safety monitoring board (GARFIELD study)].
All of the
relevant financial relationships listed have been mitigated. Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP,
FESC, FACC, FAHA Consultant/Advisory Boards: Glycardial Diagnostic[Biomarkers].
Speaker's Bureau:
Menarini [Angina pectoris];Servier [Angina pectoris].
All of the relevant financial relationships listed have
been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to
disclose.

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