Sie sind auf Seite 1von 22

Drug Class Review

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

Review prepared by:


Melissa Archer, PharmD, Clinical Pharmacist
Carin Steinvoort, PharmD, Clinical Pharmacist
Gary Oderda, PharmD, MPH, Professor

University of Utah College of Pharmacy


Copyright © 2015 by University of Utah College of Pharmacy
Salt Lake City, Utah. All rights reserved.
Table of Contents 
 
Executive Summary ......................................................................................................................... 3 
 
Introduction .................................................................................................................................... 4 
          Table 1. Antianginal Therapies .............................................................................................. 4 
          Table 2. Summary of Agents .................................................................................................. 5 
     Disease Overview ........................................................................................................................ 8 
          Table 3. Summary of Current Clinical Practice Guidelines .................................................... 9 
 
Pharmacology ............................................................................................................................... 10 
          Table 4. Pharmacokinetic Properties of the Antianginal Agents ......................................... 11 
 
Methods ........................................................................................................................................ 13 
 
Clinical Efficacy .............................................................................................................................. 13 
 
Adverse Drug Reactions ................................................................................................................ 14 
          Table 5. Drug‐Drug Interactions Reported with the Antianginal Therapies ........................ 14 
          Table 6. Adverse Events Reported with Antianginal Therapies ........................................... 15 
 
References .................................................................................................................................... 17 
 

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.

Table 1. Antianginal Therapies1,2


Drug Class  Indicated  Route of  Labeled Uses Generic 
Products  Administration  Available 
Beta‐blockers  Atenolol  Intravenous All agents: Treatment of hypertension, alone or in  Yes
Metoprolol  Oral  combination with other agents; management of 
Nadolol  angina pectoris. 
Propranolol   
Atenolol, Metoprolol, Propranolol: Secondary 
prevention postmyocardial infarction. 
 
Propranolol: Management of pheochromocytoma; 
essential tremor; supraventricular arrhythmias, 
ventricular tachycardias; migraine headache 
prophylaxis; hypertrophic subaortic stenosis; 
proliferating infantile hemangioma. 
Calcium  Amlodipine  Intravenous All agents: Treatment of hypertension; angina  Yes
Channel  Diltiazem  Oral  pectoris 
Blockers  Nicardipine   
Nifedipine  Verapamil: Treatment of supraventricular 
Verapamil  tachyarrhythmia (PSVT, atrial fibrillation/flutter 
[rate control]) 
Nitrates  Amyl Nitrite   Inhalation Treatment of angina pectoris Yes
Isosorbide  Intravenous   
Dinitrate   Oral 
Isosorbide  Rectal 
Mononitrate  Topical 
Nitroglycerin 
Miscellaneous  Ranolazine  Oral  Treatment of chronic angina No
Vasodilator 
 

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

Ischemic heart disease is a condition defined as a reduced blood supply to the


heart.13-15 Cardiac ischemia is caused by atherosclerosis, or hardening of the arteries, and
can result in angina, heart attack and death. In developed countries, ischemic heart
disease is one of the most frequently reported cardiovascular diseases and causes of
death. Angina pectoris is the most common symptom of ischemic heart disease and is
characterized as chest pain which results from an imbalance in the coronary vessels
where the oxygen demand in the heart is greater than the oxygen supplied to the heart.
The pain may be mild or intense and feel like a crushing, burning, or squeezing
discomfort that can spread to the neck or arms. Typically, the pain lasts for 5-10 minutes
and is relieved with sublingual nitroglycerin. Angina pectoris is divided into three types:
secondary angina, or effort angina, wherein inadequate blood flow during exercise or
times of stress results in chest pain; primary angina, or variant angina, wherein the
ischemia causes spasm of the coronary vessels and chest pain without increases in cardiac
demand; and unstable angina wherein a sudden worsening of the patients chronic angina
occurs.13-15 All types of angina demonstrate the same characteristic chest pains and are
relieved with the administration of nitroglycerin.

As mentioned, nitroglycerin is commonly used to treat chest pain associated with


ischemic heart disease. Nitroglycerin is an organic nitrate and considered the standard
treatment for immediate relief of angina. Overall, three drug classes are typically used in
the treatment and prevention of angina: organic nitrates, calcium channel blockers and
beta-blockers.14,15 Each of these therapeutic drug classes reduce myocardial oxygen
requirements by decreasing heart rate, blood pressure and/or contractility. Sublingual
nitroglycerin is used to treat an angina attack. Calcium channel blockers, beta-blockers
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. According to the 2012 Guidelines for Patients with
Stable Ischemic Heart Disease16, beta-blockers with or without short-acting sublingual
nitroglycerin is recommended as first-line treatment.16 The long-acting nitrates, calcium
channel blockers and ranolazine are considered second-line or add-on options in patients

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.

Table 3. Summary of Current Clinical Practice Guidelines


Guideline  Treatment Recommendations 

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:

 Relaxation of smooth muscle


 Vasodilation of the peripheral veins (primarily) and arteries
 Dilation of coronary arteries
 Reduction of cardiac oxygen demand by decreasing preload (left ventricular end-diastolic
pressure)
 Modest reduction of afterload
 Improvement of collateral flow to ischemic regions

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

Table 4. Pharmacokinetic Properties of the Antianginal Agents2,22


Agent  Bioavailability  Time to Peak  Half‐life  Metabolism   Excretion 
Amyl Nitrite   41‐45%  Onset:  Within 30 seconds  1.4‐1.5 minutes  Metabolized rapidly,  ~33% excreted in the 
    likely by hydrolytic  urine 
Duration: 3‐15 minutes  denitration 

Isosorbide  Oral immediate  Onset of action: Sublingual  Parent drug: ~1  Extensively hepatic to  Urine and feces 


Dinitrate   release  tablet: ~2‐5 minutes   hour  conjugated metabolites, 
  formulations:  Oral tablet and capsule: ~1  Metabolites   including isosorbide 5‐
Highly variable  hour   5‐mononitrate: 5  mononitrate (active) 
(10% to 90%);    hours  and 2‐mononitrate 
increases with  Duration: Sublingual tablet: 1‐ 2‐mononitrate: 2  (active) 
chronic therapy  2 hours  hours 
  Oral tablet and capsule: Up to 
Vd: 2 to 4 L/kg  8 hours 
 
Isosorbide  ~100%  Onset of action: 30‐60  ~5‐6 hours  Protein binding: <5%  Predominantly urine (2% 
Mononitrate    minutes    as unchanged drug); 
  Vd: ~0.6 L/kg    Metabolism: Hepatic  feces (1% of dose) 
Duration: Immediate release: 
≥6 hours  
Extended release: ≥12‐24 
hours  
 
Nitroglycerin   ~40%  Onset of action  ~1‐4 minutes  Protein binding: 60%   Urine (as inactive 
  Sublingual tablet and    metabolites) 
Vd: ~3 L/kg  translingual spray: 1‐3  Metabolism: Extensive 
minutes  first‐pass effect; 
Extended release: ~60  metabolized hepatically 
minutes  to glycerol di‐ and 
Topical: 15‐30 minutes  mononitrate 
Transdermal: ~30 minutes  metabolites via liver 
IV: Immediate   reductase enzyme; 
  further metabolism to 
Peak effect  glycerol and organic 
Sublingual tablet: 5 minutes  nitrate; nonhepatic 
Translingual spray: 4‐10  metabolism via red 
minutes  blood cells and vascular 
Extended release: 2.5‐4 hours  walls 
Topical: ~60 minutes 
Transdermal: 120 minutes 

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.

Table 5. Drug-Drug Interactions Reported with the Antianginal Therapies2,22,67


Medication  Interaction Description 
Organic nitrates & Ranolazine 
Avanafil*; Sildenafil*;  Clinical studies with each of the phosphodiesterase 5 (PDE5) inhibitors have found evidence that these agents 
Tadalafil*; Vardenafil*  potentiate the hypotensive effects of nitrates. Concurrent use of phosphodiesterase 5 (PDE5) inhibitors with an 
organic nitrate is contraindicated; this includes both regular and intermittent nitrate use. No safe interval between use 
of any PDE5 inhibitor and a nitrate has been identified. Based on the elimination half‐lives of the PDE5 inhibitors, 
nitrate doses should not be given within at least 24 hours of sildenafil or vardenafil, and nitrates should not be given 
within at least 48 hours of tadalafil. Avanafil US prescribing information states that in a life‐threatening situation 
where a nitrate is desired in a patient who has taken avanafil, a nitrate may be administered at least 12 hours after the 
last avanafil dose was ingested, but only with close medical supervision and monitoring. 
Bromocriptine;  Ergot alkaloids are known precipitants of angina and would be expected to oppose the antianginal effects of 
Cabergoline;  nitroglycerin.1 Additionally, nitroglycerin increases the bioavailability of dihydroergotamine and could thereby 
Dihydroergotamine;  increase the risk of adverse effects (e.g., ergotism).1,2 It is unknown whether the bioavailability of ergot derivatives 
Ergoloid Mesylates;  other than dihydroergotamine would be similarly affected. 
Ergonovine; Ergotamine*; 
Methylergonovine 
Conivaptan, Fusidic Acid,  Are strong CYP3A inhibitor and likely inhibited the metabolism of these agents, and it is expected that conivaptan 
Idelalisib, others  would have similar effects on other CYP3A4 substrates. As a result, the conivaptan prescribing information 
recommends avoiding concurrent use with drugs metabolized primarily via CYP3A.1 Also, initiation of treatment with 
any drug metabolized primarily via CYP3A should be delayed for at least 7 days following discontinuation of 
conivaptan. 
Ranolazine only 
Amiodarone; Cisapride;  Moderate Risk QTc‐Prolonging Agents may enhance the QTc‐prolonging effect of Highest Risk QTc‐Prolonging Agents.
Citalopram; Dofetilide;  The concomitant use of highest risk QTc‐prolonging agents with any other QTc‐prolonging agent should be avoided. 
Domperidone;  Many such combinations are listed contraindications for these drugs. Concomitant use is expected to substantially 
Paliperidone; Pimozide;  increase the risk for serious toxicities, including the development of torsades de pointes (TdP) or other significant 
Procainamide;  ventricular tachyarrhythmias. Patients with other risk factors present (e.g., older age, female sex, bradycardia, 
QUEtiapine; QuiNIDine;  hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations), would be at an even higher risk for 
others  these potentially life‐threatening toxicities. 

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
References

1. AHFS Drug Information, ed AHFS 2014 Drug Information. Bethesda, MD: American Society of Health-
System Pharmacists; 2014.
2. Lexi-Comp I, ed Drug Information Handbook. 21st ed. Hudson, OH: Lexi-Comp; 2014.
3. Wilson PW. Prediction of cardiovascular disease events. Cardiol Clin. Feb;29(1):1-13.
4. Srikanth S, Deedwania P. Primary and secondary prevention strategy for cardiovascular disease in diabetes
mellitus. Cardiol Clin. Feb;29(1):47-70.
5. Lardizabal JA, Deedwania P. Lipid-lowering therapy with statins for the primary and secondary prevention
of cardiovascular disease. Cardiol Clin. Feb;29(1):87-103.
6. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the
United States: a policy statement from the American Heart Association. Circulation. Mar 1;123(8):933-
944.
7. Gupta R, Deedwania P. Interventions for cardiovascular disease prevention. Cardiol Clin. Feb;29(1):15-34.
8. Franco M, Cooper RS, Bilal U, Fuster V. Challenges and opportunities for cardiovascular disease
prevention. Am J Med. Feb;124(2):95-102.
9. Ketchum K, Peterson K, Thakurta S, Low A, McDonagh MS. Drug class review: Newer Antiplatelet
Agents. Update 2. Oregon Health and Science University; 2011.
10. De Lemos JA, O'Rourke RA, Harrington R. Chapter 59. Unstable Angina and Non-ST-Segment Elevation
Myocardial Infarction. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst's the heart. 13th ed. New York:
McGraw-Hill; 2011.
11. Weitz JI. Chapter 30. Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs. In:
Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of
Therapeutics. 12th ed. New York: McGraw-Hill; 2011.
12. Weitz JI. Chapter 118. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs. In: Longo DL, Fauci AS,
Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medecine. 18th ed.
New York: McGraw-Hill; 2012.
13. Katzung BG. Vasodilators & the Treatment of Angina Pectoris. In: Katzung BG, Trevor AJ, eds. Basic &
Clinical Pharmacology. 13th ed. New York, NY: McGraw-Hill; 2015.
14. Michel T, Hoffman BB. Chapter 27. Treatment of Myocardial Ischemia and Hypertension. . In: Brunton
LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics.
12th ed. New York, NY: McGraw-Hill; 2011.
15. Depre C, Vatner SF, Gross GJ. Chapter 54. Coronary Blood Flow and Myocardial Ischemia. In: Fuster V,
Walsh RA, Harrington RA, eds. Hurst's The Heart. 13th ed. New York, NY: McGraw-Hill; 2011.
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. 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
isosorbide 2-mononitrate. Journal of cardiovascular medicine (Hagerstown, Md.). Jul 2010;11(7):486-492.
30. Is isosorbide mononitrate better than the dinitrate? Drug and therapeutics bulletin. Jan 27 1984;22(2):7-8.
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
dinitrate on platelet function and fibrinolysis in healthy volunteers. Br J Clin Pharmacol. Feb
1993;35(2):143-151.
40. Atanassova R, Spassov G, Balansky R, Boev K. Effects of isosorbide-5-mononitrate and isosorbide-2-
mononitrate on the contractile and electrical activity and on the content of cyclic nucleotides in isolated
heart muscles of the guinea-pig and dog. The Journal of pharmacy and pharmacology. Aug
1992;44(8):663-666.
41. De Caterina R, Giannessi D, Bernini W, Lazzerini G, Mazzone A, Lombardi M. In vivo actions of organic
nitrates on platelet function in humans. Zeitschrift fur Kardiologie. 1989;78 Suppl 2:56-60; discussion 64-
57.

18
42. Mukerjee N, Pietruszko R. Inactivation of human aldehyde dehydrogenase by isosorbide dinitrate. The
Journal of biological chemistry. Aug 26 1994;269(34):21664-21669.
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
Pharmacology. 12th ed. New York, NY: McGraw Hill; 2012.
1. AHFS Drug Information, ed AHFS 2014 Drug Information. Bethesda, MD: American Society of Health-
System Pharmacists; 2014.
2. Lexi-Comp I, ed Drug Information Handbook. 21st ed. Hudson, OH: Lexi-Comp; 2014.
3. Wilson PW. Prediction of cardiovascular disease events. Cardiol Clin. Feb;29(1):1-13.
4. Srikanth S, Deedwania P. Primary and secondary prevention strategy for cardiovascular disease in diabetes
mellitus. Cardiol Clin. Feb;29(1):47-70.
5. Lardizabal JA, Deedwania P. Lipid-lowering therapy with statins for the primary and secondary prevention
of cardiovascular disease. Cardiol Clin. Feb;29(1):87-103.
6. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the
United States: a policy statement from the American Heart Association. Circulation. Mar 1;123(8):933-
944.
7. Gupta R, Deedwania P. Interventions for cardiovascular disease prevention. Cardiol Clin. Feb;29(1):15-34.
8. Franco M, Cooper RS, Bilal U, Fuster V. Challenges and opportunities for cardiovascular disease
prevention. Am J Med. Feb;124(2):95-102.
9. Ketchum K, Peterson K, Thakurta S, Low A, McDonagh MS. Drug class review: Newer Antiplatelet
Agents. Update 2. Oregon Health and Science University; 2011.
10. De Lemos JA, O'Rourke RA, Harrington R. Chapter 59. Unstable Angina and Non-ST-Segment Elevation
Myocardial Infarction. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst's the heart. 13th ed. New York:
McGraw-Hill; 2011.
11. Weitz JI. Chapter 30. Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs. In:
Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of
Therapeutics. 12th ed. New York: McGraw-Hill; 2011.
12. Weitz JI. Chapter 118. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs. In: Longo DL, Fauci AS,
Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medecine. 18th ed.
New York: McGraw-Hill; 2012.
13. Katzung BG. Vasodilators & the Treatment of Angina Pectoris. In: Katzung BG, Trevor AJ, eds. Basic &
Clinical Pharmacology. 13th ed. New York, NY: McGraw-Hill; 2015.
14. Michel T, Hoffman BB. Chapter 27. Treatment of Myocardial Ischemia and Hypertension. . In: Brunton
LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics.
12th ed. New York, NY: McGraw-Hill; 2011.
15. Depre C, Vatner SF, Gross GJ. Chapter 54. Coronary Blood Flow and Myocardial Ischemia. In: Fuster V,
Walsh RA, Harrington RA, eds. Hurst's The Heart. 13th ed. New York, NY: McGraw-Hill; 2011.
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