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Antianginal Agents
24:12.08 Nitrates and Nitrites
24:04.92 Cardiac Drugs, Miscellaneous
Amyl Nitrite
Isosorbide Dinitrate (IsoDitrate ER®, others)
Isosorbide Mononitrate (Imdur®)
Nitroglycerin (Minitran®, Nitrostat®, others)
Ranolazine (Ranexa®)
Final Report
May 2015
2
Executive Summary
Introduction: A number of therapies are available for the treatment of angina, including:
beta-blockers, calcium channel blockers, nitrates and a number of miscellaneous vasodilation
agents. Four nitrates are currently available for use in the United States: amyl nitrite, isosorbide
dinitrate, isosorbide mononitrate and nitroglycerin. Ranolazine is a newer agent with a unique
mechanism of action which may also be used in the treatment and prevention of chronic angina.
Sublingual nitroglycerin is used to treat an angina attack and the long-acting nitrates
(transdermal and extended release nitroglycerin, isosorbide mononitrate, isosorbide dinitrate) are
used for prophylaxis of angina.
Ischemic heart disease is one of the most frequently reported cardiovascular diseases in
the US and angina pectoris is the most common symptom of ischemic heart disease. ACCF/AHA
Guidelines for patients with Stable Ischemic Heart Disease recommend beta-blockers with or
without short-acting sublingual nitroglycerin as first-line treatment. The long-acting nitrates and
ranolazine may be considered second-line or add-on options in patients who are not able to
tolerate beta-blockers or who require additional therapy to control angina. The nitrates and
ranolazine may also be used in the treatment of unstable angina and angina associated with heart
failure or myocardial infarction.
Clinical Efficacy: No comparative clinical evidence is available for the antianginal therapies.
When compared to placebo, the agents demonstrate efficacy in reducing the severity and
frequency of angina episodes. Clinical evidence comparing the agents to other therapies (such as
beta-blockers and calcium channel blockers) suggests the agents have similar rates of safety and
efficacy.
Adverse Drug Reactions: The most common adverse events reported with nitrate therapy are
headache and flushing. Nitrate tolerance may develop with continuous nitrate therapy and can be
avoided or overcome with daily nitrate-free intervals ranging from 12-14 hours, depending on
dosage form. Ranolazine is not associated with the development of tolerance. The most common
adverse events reported with ranolazine therapy are dizziness, headache and gastrointestinal
upset. Ranolazine is also associated with dose-related increases in the QT interval and should not
be used in patients who are at an increased risk of developing QT prolongation.
Summary: In general, the antianginal agents appear to have similar rates of efficacy and are
generally well tolerated. Development of tolerance and dosing recommendations vary between
the agents. Pharmacokinetic factors, in addition to guideline recommendations, should be used
when selecting an agent and mode of therapy with the antianginal therapies.
3
Introduction
A number of therapies are available for the treatment of angina, including: beta-blockers,
calcium channel blockers, nitrates and a number of miscellaneous vasodilation agents. This
report will include a review of the nitrates currently available for use in the United States: amyl
nitrite, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin and ranolazine. The agents
included in this review are available in oral, inhalation and injectable formulations and are used
variably, depending on severity of disease and concurrent pharmacotherapies. Table 1 provides a
summary of all therapies used in the treatment of angina and Table 2 provides a summary of the
agents included in this drug class review.
4
Table 2. Summary of Agents1,2
Drug Class Available Uses Dose Range, Adult Dose Range, Clinical Notes Generic
Formulations Pediatric Available
Amyl Nitrite Liquid, for Labeled: Coronary vasodilator in angina Angina: 2‐6 nasal inhalations from 1 crushed Not currently Given the widespread Yes
inhalation: USP: pectoris ampule; may repeat in 3‐5 minutes labeled for use in use of newer nitrate
85%‐103% (0.3 mL) pediatric patients compounds, the use
Off‐label: Cyanide toxicity; Production of Cyanide toxicity (off‐label use): 0.3 mL ampule of amyl nitrite for
changes in the intensity of heart murmurs; crushed into a gauze pad and placed in front of the Cyanide toxicity patients experiencing
Provocation of latent left ventricular patient’s mouth to inhale over 15‐30 seconds; (off‐label use): angina pectoris has
outflow tract (LVOT) gradient during repeat every minute until sodium nitrite can be Refer to adult fallen out of favor
echocardiography in patients with administered dosing
hypertrophic cardiomyopathy (HCM)
Isosorbide Oral Capsule, ER Labeled: Prevention of angina pectoris Immediate release: Initial: 5‐20 mg 2‐3 times daily; Not currently Due to slower onset Product
Dinitrate (Dilatrate‐SR®): 40 Maintenance: 10‐40 mg 2‐3 times daily or 5‐80 mg labeled for use in of action, not the drug dependent
(Dilatrate‐SR; mg Off‐label: Heart failure with reduced 2‐3 times daily pediatric patients of choice for acute
IsoDitrate ER; ejection fraction; Esophageal spastic anginal episode
Isordil Titradose) Oral Tablet disorders Sustained release: 40‐160 mg/day with nitrate free
(generic): 5 mg, 10 interval of >18 hours is recommended or 40 mg 1‐2
mg, 20 mg, 30 mg times daily; Maximum dose: 160 mg/day
Oral Tablet, ER Sublingual: 5‐10 mg every 2‐4 hours for prophylaxis
(generic): 40 mg of acute angina; may supplement with 5‐10 mg
prior to activities which may provoke an anginal
Oral Tablet, episode
sublingual (generic):
2.5 mg [DSC]
Isosorbide Oral Tablet Prevention of angina pectoris Immediate release: 5‐20 mg twice daily with the 2 Not currently Tolerance to nitrate Yes
Mononitrate (generic): 10 mg, 20 doses given 7 hours apart (eg, 8 AM and 3 PM) to labeled for use in effects develops with
(Imdur) mg decrease tolerance development pediatric patients chronic exposure;
dose escalation does
Oral Tablet, ER Extended release: 30‐60 mg given once daily in the not overcome this
(generic): 30mg, 60 morning; titrate upward as needed, giving at least effect, tolerance can
mg, 120 mg 3 days between increases; maximum daily single only be overcome by
dose: 240 mg short periods of
nitrate absence from
the body
5
Nitroglycerin Intravenous Labeled: Angina/coronary artery disease: Not currently Hemodynamic and Product
(Minitran; Nitro‐ Solution (Nitronal®): Oral: Treatment or prevention of angina Oral: 2.5‐6.5 mg 3‐4 times/day (maximum dose: 26 labeled for use in antianginal tolerance dependent
Bid; Nitro‐Dur; 1 mg/mL (25 mL, 50 pectoris mg 4 times/day) pediatric patients often develop within
Nitro‐Time; mL); (generic): 25 (IV): Treatment or prevention of angina 24‐48 hours of
Nitrolingual; mg (250 mL); 50 mg pectoris; acute decompensated heart IV: 5 mcg/minute, increase by 5 mcg/minute every Extravasation (off‐ continuous nitrate
NitroMist; (250 mL, 500 mL); failure; perioperative hypertension; 3‐5 minutes to 20 mcg/minute (maximum dose: label use; optimal administration.
Nitronal; 100 mg (250 mL); induction of intraoperative hypotension 400 mcg/minute) dosing has not Nitrate‐free interval
Nitrostat; Rectiv) 200 mg (500 mL); 5 Intra‐anal administration (Rectiv been established): (10‐12 hours/day) is
mg/mL (10 mL) ointment): Treatment of moderate‐to‐ Sublingual: 0.3‐0.6 mg every 5 minutes for Topical ointment, recommended to
severe pain associated with chronic anal maximum of 3 doses in 15 minutes; may also use 4 mm/kg applied avoid tolerance
Oral capsule, ER fissure prophylactically 5‐10 minutes prior to activities to the affected development;
(generic): 2.5 mg, which may provoke an attack area; after 8 gradually decrease
6.5 mg, 9 mg Off‐Label: Esophageal spastic disorders; hours, if no dose in patients
Sympathomimetic vasopressor Topical 2% ointment: ½‐2” 1‐2 times daily; include improvement, the receiving NTG for
Oral tablet, extravasation injury; Uterine relaxation; a nitrate free‐interval ~10‐12 hours/day dose may be prolonged period to
sublingual Short‐term management of pulmonary reapplied avoid withdrawal
(Nitrostat®): 0.3 mg, hypertension (IV); Variceal bleeding Topical patch: 0.2‐0.8 mg/hour; patch‐on period of reaction.
0.4 mg, 0.6 mg 12‐14 hours/day and patch‐off period of 10‐12
hours/day
Rectal ointment
(Rectiv): 0.4% (30 g) Translingual: 1‐2 sprays onto or under tongue
approximately every 5 minutes for maximum of 3
Transdermal doses in 15 minutes, may also be used
ointment (Nitro‐ prophylactically 5‐10 minutes prior to activities
Bid®): 2% (1 g, 30 g, which may provoke an angina attack
60 g)
Transdermal Patch,
24 Hour (generic):
0.1 mg/hr; 0.2
mg/hr; 0.4 mg/hr;
0.6 mg/hr; (Nitro‐
Dur®): 0.3 mg/hr;
0.8 mg/hr
Translingual Aerosol
(generic): 400
mcg/spray (4.1 g,
8.5 g)
Translingual
Solution (generic):
0.4 mg/spray (4.9 g,
12 g)
6
Ranolazine Oral Tablet ER, 12 Treatment of chronic angina 500 mg twice daily; may increase to 1000 mg twice Not currently Ranolazine dose No
(Ranexa®) Hour: 500 mg, 1000 daily as needed; maximum: 1000 mg twice daily labeled for use in should not exceed
mg pediatric patients 500 mg twice daily
when given
concurrently with
diltiazem,
erythromycin,
fluconazole,
verapamil and other
moderate CYP3A
inhibitors
Ranolazine dose
should be titrated to
clinical response
when used
concurrently with
P‐glycoprotein
inhibitors (eg,
cyclosporine)
Key: ER = extended release, DSC = discontinued, IV = intravenous
7
Disease Overview
Cardiovascular diseases are the most common causes of death in the United States
and are rapidly growing problems throughout the world.3-12 Diseases included in this
category are hypertension, congestive heart failure, ischemic heart disease, stroke and
peripheral arterial disease. A sedentary lifestyle, unhealthy diet, tobacco use and alcohol
abuse are some of the risk factors for developing a cardiovascular disease. According to
the American Heart Association, each day over 2000 Americans will die of a
cardiovascular disease (averaging one death every 39 seconds) and each year nearly
800,000 Americans will experience a stroke (averaging one cerebrovascular accident
every 40 seconds). Therapeutic approaches to prevent cardiovascular disease include
lifestyle modification (weight reduction, physical activity, smoking cessation), blood
pressure control, fluid management, lipid-lowering treatment, and use of antiplatelet and
antithrombotic agents.3-9
8
who are not able to tolerate beta-blockers or who require additional therapy to control
angina.16 The nitrates and ranolazine may also be used in the treatment of unstable angina
and angina associated with heart failure or myocardial infarction. Table 3 provides a
summary of the current clinical guideline recommendations for treatment of angina.
Recommendations:
ACCF/AHA/ACP/AATS/PCNA/SCAI/STS
First‐line: β‐blockers + short‐acting sublingual nitrates prn
Guideline for the Diagnosis and
Second‐line: long‐acting nitrates, calcium channel blockers, ranolazine
Management of Patients With Stable
Add‐on: β‐blockers + long‐acting nitrates, calcium channel blockers, ranolazine
Ischemic Heart Disease, 201216
Recommendations:
Institute for Clinical Systems Improvement
Daily aspirin (81‐162 mg)
(ICSI): Stable Coronary Artery Disease,
Patients with mild, stable CAD and angina:
201317
First‐line: β‐blockers + short‐acting sublingual nitrates prn
Second‐line: long‐acting nitrates
Third‐line: calcium channel blockers
Last line: ranolazine
Add‐on: β‐blockers + long‐acting nitrates
Second‐line add‐on: β‐blockers + calcium channel blockers
African Americans with NYHA class III–IV HFrEF:
ACCF/AHA Guideline for the Management
Combination of hydralazine and isosorbide dinitrate with ACE
of Heart Failure, 201318
inhibitors and beta blockers
Intravenous nitroglycerin may be useful to treat patients with STEMI
ACCF/AHA guideline for the management
and hypertension or heart failure
of ST‐elevation myocardial infarction,
There is no role for the routine use of oral nitrates in the convalescent phase of STEMI
201319
Patients with UA/NSTEMI:
Guidelines for the Management of
First‐line: beta‐blocker and ace inhibitor
Patients With Unstable Angina/Non–ST‐
Second‐line or add‐on: calcium channel blocker, angiotensin receptor
Elevation Myocardial Infarction, 201220
blocker
Patients with UA/NSTEMI and ongoing ischemic discomfort:
sublingual NTG (0.4 mg) every 5 min for a total of 3 doses
intravenous NTG is indicated in the first 48 h for treatment of
persistent ischemia, heart failure or hypertension
Patients with NSTE‐ACS:
AHA/ACC Guideline for the Management
First‐line: aspirin, beta‐blocker (sustained‐release metoprolol
of Patients With Non–ST‐Elevation Acute
succinate, carvedilol or bisoprolol, ace inhibitor, high‐intensity statin,
Coronary Syndromes, 201421
anticoagulation
Second‐line: calcium channel blocker (verapamil or diltiazem),
clopidogrel or ticagrelor
Patients with NSTE‐ACS continuing ischemic pain:
sublingual nitroglycerin (0.3‐0.4 mg) every 5 minutes for up to 3 doses
intravenous nitroglycerin for patients with persistent ischemia, heart
failure or hypertension
Key: prn‐ as needed; CAD‐ coronary artery disease; HFrEF ‐ heart failure with reduced ejection fraction; STEMI ‐ ST segment
elevation myocardial infarction; NTG ‐ nitroglycerin; UA/NSTEMI ‐ Unstable Angina/Non‐ST‐ Segment Elevation myocardial
infarction; NSTE‐ACS ‐ non–ST‐elevation acute coronary syndromes
9
Pharmacology
Organic nitrates are simple nitric and nitrous acid esters of polyalcohols.2,22,23
Nitroglycerin is considered the prototype but all of the agents have a similar mechanism of
action.14,15 Nitrates form a free radical, nitric oxide, which activates guanylate cyclase in smooth
muscle and causes myosin (MYLK) dephosphorylation, resulting in:
Tolerance may develop with continuous nitrate therapy.14,15 The development of nitrate
tolerance is not fully understood but may result from activation of a neurohormonal mechanism,
expansion of plasma volume, production of super oxide, from abnormalities in
biotransformations of nitrates or nitric oxide signaling mechanisms. Nitrate tolerance may be
avoided or overcome by daily nitrate-free intervals ranging from 12-14 hours for most long-
acting nitrates, depending on the dosage form. The addition of hydralazine to the nitrate product
may help to improve efficacy and reduce the development of tolerance.14,15
Amyl Nitrate: With the widespread use and proven efficacy for nitroglycerin and isosorbide,
the use of amyl nitrite for angina pectoris is not generally recommended. Amyl nitrate may be
used in the treatment of cyanide poisoning and works by binding to the cyanide ion to form
cyanomethemoglobin which results in release of the cytochrome oxidase and allows aerobic
metabolism to continue.2,22
Isosorbide: The isosorbide agents are indicated in the prevention of angina pectoris and are
not generally the agent of choice for acute angina episodes due to the slower onset of action (30-
60 minutes). Isosorbide is available in a dinitrate or mononitrate formulation, which is simply the
active metabolite of isosorbide dinitrate. Both formulations are given once daily (with the
extended release agents) or 2-3 times daily (with the immediate release formulations). Tolerance
can be avoided by short periods of nitrate-free intervals (10-12 hours/day).2,22
Nitroglycerin: The conventional sublingual tablet form of nitroglycerin offers relief within 1-
5 minutes and should not be chewed, crushed, or swallowed as the onset of action is quicker
when absorbed through the lining of the mouth. The sublingual tablets are stored in tightly closed
glass containers as the tablets can lose potency through volatilization and adsorption to plastic
surfaces. Nitroglycerin is also available as an translingual spray and IV formulation for
immediate relief as well as an extended release tablet and transdermal patch for prevention of
angina. To avoid the development of tolerance, the transdermal patch requires a daily 10 hour
nitrate-free period and the extended release product should be dosed with an 18 hour nitrate-free
period daily. When used in the treatment of rectal fissures, topical nitroglycerin cream works by
decreasing sphincter tone and intra-anal pressure.2,22
10
Ranolazine: The newest agent in the class, ranolazine, produces antianginal and anti-
ischemic effects without changing hemodynamic parameters, such as heart rate or blood
pressure. Ranolazine’s mechanism of action is not fully understood but it is thought to work by
inhibiting late phase sodium influx in ischemic cardiac tissue during cardiac repolarization. This
results in reduced intracellular sodium concentrations, ventricular tension and myocardial
oxygen consumption. At high doses, ranolazine may inhibit the rectifier potassium current,
prolong ventricular action and, subsequently, prolong the QT interval; caution should be taken
when using ranolazine in patients at risk for developing QT prolongation.2,22
11
IV: Immediate
Duration
Sublingual tablet and
translingual spray: >25
minutes
Extended release: 4‐8 hours
Topical: 7 hours
Transdermal: 10‐12 hours
IV: 3‐5 minutes
Ranolazine 76% Time to peak: 2‐5 hours 7 hours Protein binding: ~62% Primarily urine (75%
Metabolites mostly as metabolites;
(activity Metabolism: Extensive; <5% as unchanged drug);
undefined): 6‐22 Hepatic via CYP3A feces (25% mostly as
hours (major) and 2D6 metabolites; <5% as
(minor); intestines unchanged drug)
Key: IV‐intravenous, HTN‐ hypertension, CYP‐ cytochrome P450
12
Methods
A literature search was conducted to identify articles evaluating the antianginal agents,
searching the MEDLINE database (1950 – 2014), the Cochrane Library, and reference lists of
review articles. For the clinical efficacy section, only clinical trials published in English,
evaluating the comparative efficacy of the antianginal agents are included. Trials evaluating the
agents as monotherapy or combination therapy where adjunctive medications remained constant
throughout the trial are included. Noncomparative trials and trials comparing monotherapy with
combination regimens are excluded. The following reports were excluded (note: some were
excluded for more than 1 reason):24-31
Individual clinical trials which evaluated endpoints other than reduction of symptoms, such
as pharmacokinetics, pharmacodynamics, pharmacoeconomics or other outcomes unrelated
to reduction of symptoms.32-42
Individual trials comparing the agents in dose-finding43-51 and placebo-controlled studies51-55
or in healthy volunteers.39,56
Individual clinical trials evaluating agents or formulations not currently available in the US
or clinical trials without access to the full article.57-63
Clinical Efficacy
The efficacy of the antianginal agents has not been directly compared in any comparative
clinical trials or meta-analyses. The agents have been studied in the prevention or treatment of
angina in a number of placebo-controlled trials. Trials comparing the safety and efficacy of the
agents with other therapies, including beta-blockers and calcium channel blockers, are also
available. In a recent review of nitrates for acute heart failure syndromes (2013)64, no significant
differences in efficacy were reported between nitrate vasodilator therapy and alternative
interventions (furosemide and morphine, furosemide alone, hydralazine, beta-blockers,
intravenous nesiritide and placebo). According to the systemic review, nitrate therapy may be
associated with a lower incidence of adverse effects but no differences in symptom relief or
hemodynamic variables were demonstrated. Ranolazine has been directly compared to calcium
channel blocking therapy (amlodipine), beta-blocker therapy (atenolol) and placebo and
demonstrated statistically significant improvements in exercise stress test parameters, reduced
angina frequency and nitroglycerin use compared with placebo.65,66 In general, the antianginal
agents demonstrate efficacy in reducing the severity and frequency of angina episodes.
13
Adverse Drug Reactions
The antianginal agents are generally well-tolerated. The most common adverse events
reported with nitrate therapy include headache and flushing.2,22 Hypotension may also occur and
should be used with caution in elderly patients. Tolerance may develop with chronic antianginal
therapy and nitrate-free intervals are recommended and vary depending on agent and dosage
form. Nitrate therapy is contraindicated in patients with hypertrophic cardiomyopathy or
suspected right ventricular infarction and nitrates should not be given to patients with
hypotension, aortic stenosis, volume depletion or moderate-severe bradycardia/tachycardia.
Nitrates are also contraindicated in patients with 5'phosphodiesterase inhibitor use within the
previous 24-48 hours due to risk of severe hypotension.19 Table 5 provides a summary of
important drug interactions associated with these agents.
The most common adverse events reported with ranolazine therapy are dizziness,
constipation, headache and nausea.2,22 Ranolazine is not associated with the development of
tolerance, as seen with standard nitrate therapy. Ranolazine does produce a dose-dependent
increase in the QT interval and is contraindicated in patients with preexisting QT interval
prolongation or hepatic disease and in patients taking other drugs that prolong the QT interval.
Table 6 provides a list of the most frequent adverse events reported with each of the agents,
according to package labeling.
14
Table 6. Adverse Events Reported with Antianginal Therapies2,22,67
Agent Cardiovascular Central Nervous Dermatologic Gastrointestinal Neuromuscular Miscellaneous
System & Skeletal
Amyl Nitrite Cerebral ischemia, Dizziness, Dermatitis, Fecal Weakness Urinary incontinence,
facial flushing, headache, irritation incontinence, Hemolytic anemia,
hypotension, intracranial nausea, vomiting methemoglobinemia,
orthostatic pressure Intraocular pressure
hypotension, pallor, increased, increased, irritation,
shock, syncope, restlessness Diaphoresis
tachycardia,
vasodilation
Isosorbide Crescendo angina Headache (most ‐‐ ‐‐ ‐ Methemoglobinemia
Dinitrate (uncommon), common), (rare, overdose)
hypotension, lightheadedness
orthostatic (related to blood
hypotension, rebound pressure
hypertension changes)
(uncommon), syncope
(uncommon)
Isosorbide Angina (≤2%), flushing Headache (13% Pruritus Nausea (≤3%), Back pain, Upper respiratory
Mononitrate (≤2%), arrhythmia, to 35%), (≤2%), rash abdominal pain muscle cramps, infection (≤4%), cough
bradycardia, edema, Dizziness (≤4%), (≤2%) (≤2%), diarrhea neck pain increased (≤2%), Allergic
hyper‐/hypo‐tension, fatigue (≤4%), (≤2%), anorexia, reaction (≤2%),
orthostatic pain (≤4%), dyspepsia, taste Amblyopia, asthma,
hypotension, pallor, emotional disturbance, diaphoresis, dyspnea,
palpitation, lability (≤2%), thirst, vomiting, methemoglobinemia
tachycardia anxiety, xerostomia (rare; overdose),
concentration prostatic disorder,
impaired, sinusitis
depression,
insomnia,
nervousness,
nightmares,
paresthesia,
restlessness,
tremor, vertigo
Nitroglycerin Bradycardia, flushing, Headache Pallor, rash Nausea, Paresthesia, Dyspnea, pharyngitis,
hypotension, (common), vomiting, weakness rhinitis, Diaphoresis,
orthostatic dizziness, xerostomia Allergic reactions,
hypotension, lightheadedness, anaphylactoid reaction,
peripheral edema, blurred vision, application site irritation
syncope, tachycardia, restlessness, (patch), contact
cardiovascular vertigo dermatitis (ointment,
collapse, crescendo patch), exfoliative
angina, palpitation, dermatitis, fixed drug
rebound hypertension eruption (ointment,
patch),
methemoglobinemia
(rare; overdose), shock
Ranolazine Bradycardia (≤4%), Headache (≤6%), Hyperhidrosis Constipation Weakness Hematuria (≤4%),
hypotension (≤4%), dizziness (1% to (≤4%), (5%), abdominal (≤4%) blurred vision (≤4%),
orthostatic 6%), confusion pruritus pain (≤4%), tinnitus (≤4%), dyspnea
hypotension (≤4%), (≤4%), vertigo anorexia (≤4%), (≤4%), angioedema,
palpitation (≤4%), (≤4%), syncope dyspepsia (≤4%), decreased glycosylated
peripheral edema (≤4%), ataxia, nausea (≤4%; hemoglobin, dysuria,
(≤4%), prolonged QT hallucination, dose related), eosinophilia, increased
interval on ECG (>500 paresthesia vomiting (≤4%), blood urea nitrogen,
msec: ≤1%), torsade xerostomia increased serum
de pointes (case (≤4%) creatinine, leukopenia,
report [Morrow, pancytopenia, renal
2007]) failure,
thrombocytopenia
15
Summary
Ischemic heart disease is one of the most frequently reported cardiovascular diseases in
the US and angina pectoris is the most common symptom of ischemic heart disease. A number of
therapies are available for the treatment of angina, including: beta-blockers, calcium channel
blockers, nitrates and a number of miscellaneous vasodilation agents. Sublingual nitroglycerin is
used to treat an angina attack and long-acting nitrates (transdermal and extended release
nitroglycerin, isosorbide mononitrate, isosorbide dinitrate) are used for prophylaxis of angina.
Ranolazine is a newer agent with a unique mechanism of action which may also be used in the
treatment and prevention of chronic angina. ACCF/AHA Guidelines for patients with Stable
Ischemic Heart Disease recommend beta-blockers with or without as needed short-acting
sublingual nitroglycerin as first-line treatment. The long-acting nitrates, calcium channel
blockers and ranolazine may be considered second-line or add-on options in patients who are not
able to tolerate beta-blockers or who require additional therapy to control angina. The nitrates
and ranolazine may also be used in the treatment of unstable angina and angina associated with
heart failure or myocardial infarction.
The nitrate agents work by relaxing smooth muscle, reducing cardiac oxygen demand and
improving collateral flow to ischemic regions. Ranolazine works by inhibiting late phase sodium
influx in ischemic cardiac tissue and reducing myocardial oxygen consumption. Nitrate tolerance
may develop with continuous nitrate therapy and can be avoided or overcome with daily nitrate-
free intervals ranging from 12-14 hours, depending on dosage form. Ranolazine is not associated
with the development of tolerance. No comparative clinical evidence is available for the
antianginal therapies. Clinical evidence comparing the agents to other therapies (like beta-
blockers and calcium channel blockers) suggests the agents have similar rates of safety and
efficacy. The most common adverse events reported with nitrate therapy are headache and
flushing and the most common adverse events reported with ranolazine therapy are dizziness,
headache and gastrointestinal upset. Ranolazine is also associated with dose-related QT
prolongation. In general, the antianginal agents appear to have similar rates of efficacy and are
generally well tolerated but development of tolerance and dosing recommendations vary between
the agents. Pharmacokinetic factors, in addition to guideline recommendations, should be used
when selecting an agent and mode of therapy with the antianginal therapies.
16
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diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of
the American College of Cardiology Foundation/American Heart Association task force on practice
guidelines, and the American College of Physicians, American Association for Thoracic Surgery,
Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions,
and Society of Thoracic Surgeons. Circulation. Dec 18 2012;126(25):3097-3137.
17. Goblirsch G, Bershow S, Cummings K, et al. Stable Coronary Artery Disease.: Institute for Clinical
Systems Improvement; 2013.
18. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a
report of the American College of Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines. Journal of the American College of Cardiology. Oct 15 2013;62(16):e147-239.
19. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-
elevation myocardial infarction: a report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines. Circulation. Jan 29 2013;127(4):e362-425.
20. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the
ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation
myocardial infarction: a report of the American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines. Circulation. Jun 11 2013;127(23):e663-828.
21. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients
with non-ST-elevation acute coronary syndromes: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. Dec 23
2014;130(25):e344-426.
22. McEvoy GK, Snow EK, Kester L, Litvak K, Miller J, Welsh OH, eds. AHFS 2014 Drug Information.
Bethesda, MD: American Society of Health-System Pharmacists; 2014.
23. Bogaert MG. Clinical pharmacokinetics of nitrates. Cardiovascular drugs and therapy / sponsored by the
International Society of Cardiovascular Pharmacotherapy. Oct 1994;8(5):693-699.
24. Ninomiya Y, Hamasaki S, Saihara K, et al. Comparison of effect between nitrates and calcium channel
antagonist on vascular function in patients with normal or mildly diseased coronary arteries. Heart and
vessels. Mar 2008;23(2):83-90.
25. Kaplan K, Davison R, Parker M, Przybylek J, Teagarden JR, Lesch M. Intravenous nitroglycerin for the
treatment of angina at rest unresponsive to standard nitrate therapy. The American journal of cardiology.
Mar 1 1983;51(5):694-698.
26. Hall R, Chong C. A double-blind, parallel-group study of amlodipine versus long-acting nitrate in the
management of elderly patients with stable angina. Cardiology. 2001;96(2):72-77.
27. Shapira OM, Alkon JD, Macron DS, et al. Nitroglycerin is preferable to diltiazem for prevention of
coronary bypass conduit spasm. The Annals of thoracic surgery. Sep 2000;70(3):883-888; discussion 888-
889.
28. Heidenreich PA, McDonald KM, Hastie T, et al. Meta-analysis of trials comparing beta-blockers, calcium
antagonists, and nitrates for stable angina. JAMA : the journal of the American Medical Association. May
26 1999;281(20):1927-1936.
29. Raddino R, Caretta G, Bonadei I, Teli M, Vizzardi E, Cas LD. Differences between nitrates: role of
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31. Ankier SI, Fay L, Warrington SJ, Woodings DF. A multicentre open comparison of isosorbide-5-
mononitrate and nifedipine given prophylactically to general practice patients with chronic stable angina
pectoris. J Int Med Res. Mar-Apr 1989;17(2):172-178.
32. Macedo PG, Asirvatham SJ, Maia L, et al. Comparison of a shortened isosorbide dinitrate-potentiated
head-up tilt testing with the conventional protocol: tolerance and diagnostic accuracy. Pacing and clinical
electrophysiology : PACE. Aug 2012;35(8):1005-1011.
33. Holmes AS, Chirkov YY, Willoughby SR, Poropat S, Pereira J, Horowitz JD. Preservation of platelet
responsiveness to nitroglycerine despite development of vascular nitrate tolerance. Br J Clin Pharmacol.
Oct 2005;60(4):355-363.
34. Kosmicki MA, Szwed H, Sadowski Z. Anti-ischaemic response to sublingual nitroglycerin during oral
administration of isosorbide dinitrate in patients with stable angina pectoris: when does cross-tolerance
occur? Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular
Pharmacotherapy. Jan 2004;18(1):47-55.
35. Khanlari B, Linder L, Haefeli WE. Local effect of transdermal isosorbide dinitrate ointment on hand vein
diameter. European journal of clinical pharmacology. Dec 2001;57(10):701-704.
36. Nino J, Villar JC, Tahvanainen KU, Kahonen M, Kuusela TA, Morillo CA. Vasovagal susceptibility to
nitrate or isoproterenol head-up tilt. The American journal of cardiology. Dec 1 2001;88(11):1326-1330.
37. Webb DJ, Muirhead GJ, Wulff M, Sutton JA, Levi R, Dinsmore WW. Sildenafil citrate potentiates the
hypotensive effects of nitric oxide donor drugs in male patients with stable angina. Journal of the American
College of Cardiology. Jul 2000;36(1):25-31.
38. Pfister M, Seiler C, Fleisch M, Gobel H, Luscher T, Meier B. Nitrate induced coronary vasodilatation:
differential effects of sublingual application by capsule or spray. Heart. Oct 1998;80(4):365-369.
39. Wallen NH, Larsson PT, Broijersen A, Andersson A, Hjemdahl P. Effects of an oral dose of isosorbide
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40. Atanassova R, Spassov G, Balansky R, Boev K. Effects of isosorbide-5-mononitrate and isosorbide-2-
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41. De Caterina R, Giannessi D, Bernini W, Lazzerini G, Mazzone A, Lombardi M. In vivo actions of organic
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18
42. Mukerjee N, Pietruszko R. Inactivation of human aldehyde dehydrogenase by isosorbide dinitrate. The
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43. Parker JO. Eccentric dosing with isosorbide-5-mononitrate in angina pectoris. The American journal of
cardiology. Oct 15 1993;72(12):871-876.
44. Thadani U, Maranda CR, Amsterdam E, et al. Lack of pharmacologic tolerance and rebound angina
pectoris during twice-daily therapy with isosorbide-5-mononitrate. Annals of internal medicine. Mar 1
1994;120(5):353-359.
45. Chrysant SG, Glasser SP, Bittar N, et al. Efficacy and safety of extended-release isosorbide mononitrate for
stable effort angina pectoris. The American journal of cardiology. Dec 1 1993;72(17):1249-1256.
46. DeMots H, Glasser SP. Intermittent transdermal nitroglycerin therapy in the treatment of chronic stable
angina. Journal of the American College of Cardiology. Mar 15 1989;13(4):786-795.
47. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with
heart failure. The New England journal of medicine. Nov 11 2004;351(20):2049-2057.
48. Anand IS, Tam SW, Rector TS, et al. Influence of blood pressure on the effectiveness of a fixed-dose
combination of isosorbide dinitrate and hydralazine in the African-American Heart Failure Trial. Journal of
the American College of Cardiology. Jan 2 2007;49(1):32-39.
49. Cohn JN, Tam SW, Anand IS, et al. Isosorbide dinitrate and hydralazine in a fixed-dose combination
produces further regression of left ventricular remodeling in a well-treated black population with heart
failure: results from A-HeFT. Journal of cardiac failure. Jun 2007;13(5):331-339.
50. Colvin-Adams M, Taylor AL. Isosorbide dinitrate-hydralazine improves outcomes in African Americans
with heart failure. Cleveland Clinic journal of medicine. Mar 2007;74(3):227-234.
51. Taylor AL, Ziesche S, Yancy CW, et al. Early and sustained benefit on event-free survival and heart failure
hospitalization from fixed-dose combination of isosorbide dinitrate/hydralazine: consistency across
subgroups in the African-American Heart Failure Trial. Circulation. Apr 3 2007;115(13):1747-1753.
52. Thadani U, Ezekowitz M, Fenney L, Chiang YK. Double-blind efficacy and safety study of a novel anti-
ischemic agent, ranolazine, versus placebo in patients with chronic stable angina pectoris. Ranolazine
Study Group. Circulation. Aug 1994;90(2):726-734.
53. Thadani U, Opie LH. Nitrates for unstable angina. Cardiovascular drugs and therapy / sponsored by the
International Society of Cardiovascular Pharmacotherapy. Oct 1994;8(5):719-726.
54. Karlberg KE, Saldeen T, Wallin R, Henriksson P, Nyquist O, Sylven C. Intravenous nitroglycerin reduces
ischaemia in unstable angina pectoris: a double-blind placebo-controlled study. Journal of internal
medicine. Jan 1998;243(1):25-31.
55. Yancy CW, Ghali JK, Braman VM, et al. Evidence for the continued safety and tolerability of fixed-dose
isosorbide dinitrate/hydralazine in patients with chronic heart failure (the extension to African-American
Heart Failure Trial). The American journal of cardiology. Aug 15 2007;100(4):684-689.
56. Hutt V, Theodor R, Pabst G, Lutz D, Bonn R, Fritschi E. Bioavailability and pharmacokinetics of a new
isosorbide dinitrate spray preparation in healthy volunteers. Arzneimittel-Forschung. Aug 1993;43(8):842-
846.
57. Bray CL, Jain S, Faragher EB, et al. A comparison of buccal nitroglycerin and sublingual nitroglycerin in
the prophylaxis and treatment of exertional (situation-provoked) angina pectoris. European heart journal.
May 1991;12 Suppl A:16-20.
58. Ryden L, Schaffrath R. Buccal versus sublingual nitroglycerin administration in the treatment of angina
pectoris: a multicentre study. European heart journal. Sep 1987;8(9):995-1001.
59. Dellborg M, Gustafsson G, Swedberg K. Buccal versus intravenous nitroglycerin in unstable angina
pectoris. European journal of clinical pharmacology. 1991;41(1):5-9.
60. Tankova L, Yoncheva K, Kovatchki D, Doytchinova I. Topical anal fissure treatment: placebo-controlled
study of mononitrate and trinitrate therapies. International journal of colorectal disease. Apr
2009;24(4):461-464.
61. Dragoni S, Gori T, Lisi M, et al. Pentaerythrityl tetranitrate and nitroglycerin, but not isosorbide
mononitrate, prevent endothelial dysfunction induced by ischemia and reperfusion. Arteriosclerosis,
thrombosis, and vascular biology. Sep 2007;27(9):1955-1959.
62. Zhu WL, Shan YD, Guo JX, et al. Double-blind, multicenter, active-controlled, randomized clinical trial to
assess the safety and efficacy of orally administered nicorandil in patients with stable angina pectoris in
China. Circulation journal : official journal of the Japanese Circulation Society. Jun 2007;71(6):826-833.
63. Rayman G, Baker NR, Krishnan ST. Glyceryl trinitrate patches as an alternative to isosorbide dinitrate
spray in the treatment of chronic painful diabetic neuropathy. Diabetes care. Sep 2003;26(9):2697-2698.
19
64. Wakai A, McCabe A, Kidney R, et al. Nitrates for acute heart failure syndromes. Cochrane Database Syst
Rev. 2013;8:Cd005151.
65. Banon D, Filion KB, Budlovsky T, Franck C, Eisenberg MJ. The usefulness of ranolazine for the treatment
of refractory chronic stable angina pectoris as determined from a systematic review of randomized
controlled trials. The American journal of cardiology. Mar 15 2014;113(6):1075-1082.
66. Savarese G, Rosano G, D'Amore C, et al. Effects of ranolazine in symptomatic patients with stable
coronary artery disease. A systematic review and meta-analysis. International journal of cardiology. Nov
15 2013;169(4):262-270.
67. Ives HE. Chapter 15. Diuretic Agents. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical
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5. Lardizabal JA, Deedwania P. Lipid-lowering therapy with statins for the primary and secondary prevention
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15. Depre C, Vatner SF, Gross GJ. Chapter 54. Coronary Blood Flow and Myocardial Ischemia. In: Fuster V,
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16. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the
diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of
the American College of Cardiology Foundation/American Heart Association task force on practice
guidelines, and the American College of Physicians, American Association for Thoracic Surgery,
Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions,
and Society of Thoracic Surgeons. Circulation. Dec 18 2012;126(25):3097-3137.
17. Goblirsch G, Bershow S, Cummings K, et al. Stable Coronary Artery Disease.: Institute for Clinical
Systems Improvement; 2013.
18. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a
report of the American College of Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines. Journal of the American College of Cardiology. Oct 15 2013;62(16):e147-239.
19. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-
elevation myocardial infarction: a report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines. Circulation. Jan 29 2013;127(4):e362-425.
20
20. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the
ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation
myocardial infarction: a report of the American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines. Circulation. Jun 11 2013;127(23):e663-828.
21. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients
with non-ST-elevation acute coronary syndromes: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. Dec 23
2014;130(25):e344-426.
22. McEvoy GK, Snow EK, Kester L, Litvak K, Miller J, Welsh OH, eds. AHFS 2014 Drug Information.
Bethesda, MD: American Society of Health-System Pharmacists; 2014.
23. Ninomiya Y, Hamasaki S, Saihara K, et al. Comparison of effect between nitrates and calcium channel
antagonist on vascular function in patients with normal or mildly diseased coronary arteries. Heart and
vessels. Mar 2008;23(2):83-90.
24. Kaplan K, Davison R, Parker M, Przybylek J, Teagarden JR, Lesch M. Intravenous nitroglycerin for the
treatment of angina at rest unresponsive to standard nitrate therapy. The American journal of cardiology.
Mar 1 1983;51(5):694-698.
25. Hall R, Chong C. A double-blind, parallel-group study of amlodipine versus long-acting nitrate in the
management of elderly patients with stable angina. Cardiology. 2001;96(2):72-77.
26. Shapira OM, Alkon JD, Macron DS, et al. Nitroglycerin is preferable to diltiazem for prevention of
coronary bypass conduit spasm. The Annals of thoracic surgery. Sep 2000;70(3):883-888; discussion 888-
889.
27. Heidenreich PA, McDonald KM, Hastie T, et al. Meta-analysis of trials comparing beta-blockers, calcium
antagonists, and nitrates for stable angina. JAMA : the journal of the American Medical Association. May
26 1999;281(20):1927-1936.
28. Macedo PG, Asirvatham SJ, Maia L, et al. Comparison of a shortened isosorbide dinitrate-potentiated
head-up tilt testing with the conventional protocol: tolerance and diagnostic accuracy. Pacing and clinical
electrophysiology : PACE. Aug 2012;35(8):1005-1011.
29. Holmes AS, Chirkov YY, Willoughby SR, Poropat S, Pereira J, Horowitz JD. Preservation of platelet
responsiveness to nitroglycerine despite development of vascular nitrate tolerance. Br J Clin Pharmacol.
Oct 2005;60(4):355-363.
30. Kosmicki MA, Szwed H, Sadowski Z. Anti-ischaemic response to sublingual nitroglycerin during oral
administration of isosorbide dinitrate in patients with stable angina pectoris: when does cross-tolerance
occur? Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular
Pharmacotherapy. Jan 2004;18(1):47-55.
31. Khanlari B, Linder L, Haefeli WE. Local effect of transdermal isosorbide dinitrate ointment on hand vein
diameter. European journal of clinical pharmacology. Dec 2001;57(10):701-704.
32. Nino J, Villar JC, Tahvanainen KU, Kahonen M, Kuusela TA, Morillo CA. Vasovagal susceptibility to
nitrate or isoproterenol head-up tilt. The American journal of cardiology. Dec 1 2001;88(11):1326-1330.
33. Webb DJ, Muirhead GJ, Wulff M, Sutton JA, Levi R, Dinsmore WW. Sildenafil citrate potentiates the
hypotensive effects of nitric oxide donor drugs in male patients with stable angina. Journal of the American
College of Cardiology. Jul 2000;36(1):25-31.
34. Pfister M, Seiler C, Fleisch M, Gobel H, Luscher T, Meier B. Nitrate induced coronary vasodilatation:
differential effects of sublingual application by capsule or spray. Heart. Oct 1998;80(4):365-369.
35. Parker JO. Eccentric dosing with isosorbide-5-mononitrate in angina pectoris. The American journal of
cardiology. Oct 15 1993;72(12):871-876.
36. Thadani U, Maranda CR, Amsterdam E, et al. Lack of pharmacologic tolerance and rebound angina
pectoris during twice-daily therapy with isosorbide-5-mononitrate. Annals of internal medicine. Mar 1
1994;120(5):353-359.
37. Chrysant SG, Glasser SP, Bittar N, et al. Efficacy and safety of extended-release isosorbide mononitrate for
stable effort angina pectoris. The American journal of cardiology. Dec 1 1993;72(17):1249-1256.
38. DeMots H, Glasser SP. Intermittent transdermal nitroglycerin therapy in the treatment of chronic stable
angina. Journal of the American College of Cardiology. Mar 15 1989;13(4):786-795.
39. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with
heart failure. The New England journal of medicine. Nov 11 2004;351(20):2049-2057.
21
40. Anand IS, Tam SW, Rector TS, et al. Influence of blood pressure on the effectiveness of a fixed-dose
combination of isosorbide dinitrate and hydralazine in the African-American Heart Failure Trial. Journal of
the American College of Cardiology. Jan 2 2007;49(1):32-39.
41. Cohn JN, Tam SW, Anand IS, et al. Isosorbide dinitrate and hydralazine in a fixed-dose combination
produces further regression of left ventricular remodeling in a well-treated black population with heart
failure: results from A-HeFT. Journal of cardiac failure. Jun 2007;13(5):331-339.
42. Colvin-Adams M, Taylor AL. Isosorbide dinitrate-hydralazine improves outcomes in African Americans
with heart failure. Cleveland Clinic journal of medicine. Mar 2007;74(3):227-234.
43. Taylor AL, Ziesche S, Yancy CW, et al. Early and sustained benefit on event-free survival and heart failure
hospitalization from fixed-dose combination of isosorbide dinitrate/hydralazine: consistency across
subgroups in the African-American Heart Failure Trial. Circulation. Apr 3 2007;115(13):1747-1753.
44. Thadani U, Ezekowitz M, Fenney L, Chiang YK. Double-blind efficacy and safety study of a novel anti-
ischemic agent, ranolazine, versus placebo in patients with chronic stable angina pectoris. Ranolazine
Study Group. Circulation. Aug 1994;90(2):726-734.
45. Thadani U, Opie LH. Nitrates for unstable angina. Cardiovascular drugs and therapy / sponsored by the
International Society of Cardiovascular Pharmacotherapy. Oct 1994;8(5):719-726.
46. Karlberg KE, Saldeen T, Wallin R, Henriksson P, Nyquist O, Sylven C. Intravenous nitroglycerin reduces
ischaemia in unstable angina pectoris: a double-blind placebo-controlled study. Journal of internal
medicine. Jan 1998;243(1):25-31.
47. Yancy CW, Ghali JK, Braman VM, et al. Evidence for the continued safety and tolerability of fixed-dose
isosorbide dinitrate/hydralazine in patients with chronic heart failure (the extension to African-American
Heart Failure Trial). The American journal of cardiology. Aug 15 2007;100(4):684-689.
48. Bray CL, Jain S, Faragher EB, et al. A comparison of buccal nitroglycerin and sublingual nitroglycerin in
the prophylaxis and treatment of exertional (situation-provoked) angina pectoris. European heart journal.
May 1991;12 Suppl A:16-20.
49. Ryden L, Schaffrath R. Buccal versus sublingual nitroglycerin administration in the treatment of angina
pectoris: a multicentre study. European heart journal. Sep 1987;8(9):995-1001.
50. Dellborg M, Gustafsson G, Swedberg K. Buccal versus intravenous nitroglycerin in unstable angina
pectoris. European journal of clinical pharmacology. 1991;41(1):5-9.
51. Tankova L, Yoncheva K, Kovatchki D, Doytchinova I. Topical anal fissure treatment: placebo-controlled
study of mononitrate and trinitrate therapies. International journal of colorectal disease. Apr
2009;24(4):461-464.
52. Dragoni S, Gori T, Lisi M, et al. Pentaerythrityl tetranitrate and nitroglycerin, but not isosorbide
mononitrate, prevent endothelial dysfunction induced by ischemia and reperfusion. Arteriosclerosis,
thrombosis, and vascular biology. Sep 2007;27(9):1955-1959.
53. Zhu WL, Shan YD, Guo JX, et al. Double-blind, multicenter, active-controlled, randomized clinical trial to
assess the safety and efficacy of orally administered nicorandil in patients with stable angina pectoris in
China. Circulation journal : official journal of the Japanese Circulation Society. Jun 2007;71(6):826-833.
54. Rayman G, Baker NR, Krishnan ST. Glyceryl trinitrate patches as an alternative to isosorbide dinitrate
spray in the treatment of chronic painful diabetic neuropathy. Diabetes care. Sep 2003;26(9):2697-2698.
55. Banon D, Filion KB, Budlovsky T, Franck C, Eisenberg MJ. The usefulness of ranolazine for the treatment
of refractory chronic stable angina pectoris as determined from a systematic review of randomized
controlled trials. The American journal of cardiology. Mar 15 2014;113(6):1075-1082.
56. Ives HE. Chapter 15. Diuretic Agents. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical
Pharmacology. 12th ed. New York, NY: McGraw Hill; 2012.
22