Professional Documents
Culture Documents
FACULTY:
Nicole K. Brogden, PharmD
PGY1 Pharmacy Resident, University of
Kentucky HealthCare, Lexington, Kentucky
DISCLAIMER:
Participants have an implied responsibility to use the newly acquired information to enhance
patient outcomes and their own professional development. The information presented in this
activity is not meant to serve as a guideline for patient management. Any procedures,
medications, or other courses of diagnosis or treatment discussed or suggested in this activity
Angina is the most frequent symptom of coronary artery disease (CAD), prompting the majority of
patients with CAD to seek medical attention.1 Angina is classically characterized as substernal
discomfort, and patients often describe their pain using terms such as “squeezing, suffocating, or
pressure-like.”2 A diagnosis of chronic stable angina (CSA) includes left anterior chest discomfort
that is predictable and reproducible after emotional stress and/or physical activity; the associated
anginal symptoms are typically relieved by either sublingual nitroglycerin or cessation of the
exacerbating circumstances. Symptoms are typically worse in cold conditions or following
meals.2,3 When a patient presents with chest pain, the initial evaluation should include a detailed
history, physical examination, and other appropriate tests in order to determine the patient’s
probability of having significant CAD versus acute myocardial infarction (MI).2 A detailed history of
the pain should be elicited from the patient, including the nature of the pain, precipitating factors,
duration, and relief with rest or nitroglycerin.3,4
A patient presenting with acute onset of angina should also be evaluated for acute coronary
syndrome. The following discussion will focus only on the treatment of CSA.
Symptoms originate from regional myocardial ischemia that arises from inadequate coronary
perfusion. This type of angina is typically, although not always, caused by increased myocardial
oxygen requirements.3,4 An increase in myocardial oxygen demand is created during increased
activity or stress, leading to a supply-demand mismatch and resulting in ischemia. Progression of
atherosclerosis in the coronary arteries can lead to plaque deposition external to the lumen,
ultimately intruding into the lumen, causing obstruction, and, therefore, angina (FIGURE 1).4
Classification of Angina
Stable angina can be described as classic (typical), atypical, nonanginal, and noncardiac; each
type of angina presents with distinct symptoms.2-4 Classic or typical angina involves three distinct
characteristics: 1) substernal chest discomfort or pain that has a characteristic quality and
duration, which is 2) brought on by emotional stress or physical activity, and is 3) usually relieved
by either rest or nitroglycerin. Atypical angina presents as chest pain that contains two out of the
three characteristics of stable angina and is more common in women, elderly patients, and
patients with diabetes. Noncardiac angina meets one or none of the characteristics of classic
angina, and the differential diagnosis should include gastroesophageal reflux disease (GERD),
peptic ulcer disease, mitral valve prolapse, and biliary disease.2-4
Table 1
Canadian Cardiovascular Society Angina Grading Scale
Angina Accompanying Symptoms
Classification
Source: Reference 1.
In addition to the pharmacologic options and standards of care described by the 2002 ACC/AHA
guidelines, ranolazine was approved in January 2006 by the FDA as a novel treatment option for
CSA in patients who have not achieved adequate control of angina symptoms with standard
therapies.6 (These pharmacologic treatments are summarized in TABLE 2.) Nonpharmacologic
interventions for CSA, such as percutaneous coronary intervention and lifestyle modifications,
remain central to the overall management of the patient and will be discussed as well.
Despite differing amounts of alpha- and beta-blocking properties, all of the beta-blockers are
essentially thought to be equally effective for the treatment of CSA, although not all are FDA
approved for this indication.7 The beta-blockers exert their antianginal effects in a dose-dependent
manner; thus, therapy must be titrated to goal, which is a resting heart rate of 50 to 60 beats per
minute (bpm) and an exercise heart rate of less than 100 bpm.4
There are several absolute contraindications to beta-blocker therapy, including sick sinus
syndrome, severe bradycardia or atrioventricular block, and unstable heart failure (TABLE 2).
Relative contraindications to beta-blockers include asthma, peripheral vascular disease, and
depression.7 General side effects of this class include fatigue, exercise intolerance, brady-cardia,
hypotension, altered glucose metabolism, and worsening claudication.5,7
Calcium Channel Blockers: In general, the calcium channel antagonists (commonly known as
calcium channel blockers, or CCBs), are equally effective in the management of stable angina.9-12
These agents exert their antianginal effects via inhibition of calcium entry into myocardial tissue,
resulting in dilation of both systemic and coronary arteries that leads to an increase in coronary
blood flow and thus decreases myocardial oxygen consumption.3,4
The CCBs should be considered first-line therapy in situations when beta-blocker therapy is not
indicated, including when patients have absolute contraindications to beta-blockers or are unable
to tolerate therapy because of adverse events.5 CCBs can also be used as add-on therapy in
patients with inadequate control of anginal symptoms on monotherapy with a beta-blocker.5 In
general, the short-acting dihydropyridine CCBs should not be used for the treatment of angina
because of their potential to produce ischemia through rebound activation of the sympathetic
nervous system.13
Generally, all CCBs cause similar adverse events, including peripheral edema, worsening of heart
failure, hypotension, and constipation (TABLE 2). Various CCBs have agent-specific adverse
events due to differences in pharmacology (dihydropyridine versus nondihydropyridine), which
include excessive reflex tachycardia (e.g., nifedipine) and bradyarrhythmias (e.g., diltiazem and
verapamil). Due to differences in the adverse-effect profiles and peripheral and central
hemodynamic effects, the initial choice of a calcium channel blocker should be carefully
considered.
There are many different nitrate preparations, most of which are FDA approved for the treatment
of angina (TABLE 2). The most commonly utilized agent is sublingual nitroglycerin, which has an
elimination half-life of only a few minutes and is the treatment of choice to halt acute anginal
episodes. The instability of nitroglycerin tablets makes nitroglycerin spray an attractive alternative
for more active individuals or those with chronically dry mouth. In vivo, nitroglycerin is
extrahepatically converted rapidly to longer-acting dinitrates, which are biologically active.14
However, when isosorbide dinitrate is administered orally, it must be converted by the liver into
active mononitrates. Isosorbide dinitrate given sublingually has an antianginal effect lasting about
one hour and, when ingested, will last up to six hours. The longest-acting oral preparation is the
biologically active formulation isosorbide mononitrate, which is also available in a sustained-
release (SR) preparation.
Unlike beta-blockers, nitrates have not demonstrated the ability to reduce MIs or death. However,
studies have shown increased exercise duration with isosorbide mononitrate 120 to 240 mg daily
and isosorbide dinitrate 15 to 120 mg administered several times a day.15,16 Nitrates are also ideal
when used in combination with beta-blockers, which may prevent the nitrate adverse effect of
reflex tachycardia.17 When used in combination with calcium channel blockers, hypotension may
be more profound, but this combination has also demonstrated positive effects on exercise
tolerance. Other important interactions causing profound hypotension include concomitant use of
phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil), a combination that should be
avoided for up to 24 hours after administration of sildenafil or vardenafil, and 48 hours after long-
acting tadalafil.18
However, there is a potentially beneficial drug interaction with hydralazine, which lessens nitrate
tolerance by decreasing nitric oxide degradation.19 Nitrate tolerance was first noticed by Brunton
and published in the Lancet in 1867.20 Tachyphylaxis is the primary reason for therapy failure with
longer-acting preparations, but it can be circumvented by providing a 10-to 12-hour nitrate-free
interval or by concurrent administration with hydralazine.21 With so many options for
administration, nitrates are ideal to treat angina in patients without compelling indications for
previously discussed classes or as adjunct therapy.
Ranolazine
On January 1, 2006, the FDA approved ranolazine as a new treatment option for patients with
CSA. Its mechanism of action remains unknown, although the antianginal effects are produced
without any significant changes in hemodynamic properties such as heart rate and blood
pressure.6
Despite some uncertainty regarding the exact mechanism of action, ranolazine is thought to exert
its effects by altering the production of adenosine triphosphate (ATP) away from oxidation of fatty
acids, thus favoring the more oxygen-efficient oxidation of carbohydrates.22 During myocardial
ischemia, the levels of fatty acids rise suddenly, thus promoting their uptake and oxidation in the
myocardial tissue.22 The phosphorylation of ATP during the oxidation of fatty acids requires more
oxygen than carbohydrate oxidation, ultimately leading to an inefficient use of the available
oxygen supply. A shift in metabolism from fatty acid to carbohydrate oxidation theoretically
promotes more efficient use of oxygen and would potentially lessen ischemia.22,23 In addition,
ranolazine has been shown to inhibit the late phase of the inward sodium current during
repolarization of cardiac tissue, which may also reduce myocardial ischemia and control
symptoms of angina.24 Fatty acid metabolism by myocytes also produces potentially harmful
byproducts, thereby suggesting a potential role for ranolazine in reducing harmful cardiac events.
Ranolazine undergoes significant metabolism in the liver and gut, with a half-life of approximately
seven hours.6 Nearly 75% of the drug is excreted in the urine, while the remainder is excreted via
feces. Ranolazine is currently contraindicated in patients with preexisting long QT syndrome
(irregular electrical activity of the heart that places patients at risk for ventricular arrhythmias) or in
those receiving QT-prolonging drugs. Ranolazine is also contraindicated in patients receiving
concurrent therapy with CYP3A inhibitors (including diltiazem) and in patients with severe hepatic
impairment. No cases of torsades de pointes (a rare form of ventricular tachycardia) have been
reported to date.6
Ranolazine is available as an SR oral tablet that can be taken with or without regard to meals
(TABLE 2). Therapy is initiated at 500 mg bid and titrated up to 1,000 mg bid, based on clinical
symptoms (maximum dose is 1,000 mg bid). In general, concurrent therapy with other antianginal
treatments is well tolerated.6
To date, four major trials have been published describing the efficacy and safety of ranolazine:
the Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) trial,22 the Combination
Assessment of Ranolazine in Stable Angina (CARISA) trial,23 the Efficacy of Ranolazine in
Chronic Angina (ERICA) trial,25 and the Metabolic Efficiency with Ranolazine for Less Ischemia in
Non-ST Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-
TIMI 36) trial.24 A brief description of each of these trials is included in the following paragraphs.
Table 2
Pharmacologic Treatments for Chronic Stable Angina
Drug Mechanism Place in Specific Agents Side Contraindications
Class of Action Therapy (Dosing) Effects
Ranolazine Mechanism of Combination Initiate at 500 mg bid; Dizziness, Severe hepatic dys-
action therapy with titrate up to max dose headache, function, concurrent use
not amlodipine, of constipation, of QT-interval-prolonging
clear; possible nitrates, 1,000 mg bid nausea agents or preexisting QT
shift or beta- interval prolongation at
in the production blockers baseline, concurrent
of in patients therapy with CYP3A
ATP away from not
oxidation well
of controlled
fatty acids, thus with
favoring the monotherapy
more on these
oxygen-efficient agents
oxidation
of carbohydrates
AV: atrioventricular; ER: extended-release; max: maximum; IR: immediate-release: SR: sustained-release; DHP: dihydropyridine;
MI: myocardial infarction; PDEs: phosphodiesterase inhibitors; ATP: adenosine triphosphate.
Source: References 3, 6.
MARISA: The MARISA trial was the first placebo-controlled trial to examine ranolazine SR as
monotherapy in patients with chronic angina. All subjects had at least a three-month history of
exertional angina that was responsive to beta-blockers, CCBs, and/or long-acting nitrates. The
primary end point of the trial was total exercise duration at trough of ranolazine plasma
concentrations. The authors concluded that doses of 500 to 1,500 mg of ranolazine improved
exercise performance significantly and delayed or prevented the ECG evidence and symptoms of
myocardial ischemia (during exercise tests of patients with CSA). These effects occurred with
minimal or no effects on heart rate and blood pressure.22
CARISA: The CARISA trial was a double-blind, three-group parallel trial designed to assess the
antianginal and anti-ischemic effects of ranolazine in patients with anginal symptoms despite
standard treatment with atenolol, diltiazem, or amlodipine. The primary end point of the trial was
to compare the effects of placebo versus ranolazine with regard to exercise duration when
ranolazine levels were at a trough (i.e., 12 hours after administration of the dose). Subjects
discontinued all antianginal drugs except those required for background therapy (atenolol,
amlodipine, or diltiazem), and the subjects were randomized to receive ranolazine or placebo.
The trial met the primary end point, as the duration of exercise in those patients taking ranolazine
was increased over placebo.23
ERICA: The ERICA trial was a prospective, randomized, double-blind trial of patients
experiencing three or more anginal attacks per week despite maximal therapy with amlodipine.
Frequency of angina episodes during the six-week treatment period was the primary end point;
efficacy was assessed by the consumption of nitroglycerin per week and the Seattle Angina
Questionnaire. The results of the trial displayed a significant reduction in the frequency of angina
episodes and consumption of nitroglycerin in the ranolazine group. Patients who experienced
more frequent angina displayed a more profound treatment effect.25
MERLIN-TIMI 36: The MERLIN-TIMI 36 trial was a randomized, controlled trial of hospitalized
patients with non-ST elevation acute coronary syndrome. The primary objective of the study was
to evaluate the effect of ranolazine (compared to placebo) on the composite of recurrent ischemic
events or cardiovascular death; ECG measurements were used to assess the incidence of
clinically significant arrhythmias. The results of the MERLIN-TIMI 36 trial failed to meet the
primary end point. However, ranolazine did demonstrate non-significant decrease in the incidence
of sudden cardiac death when compared to placebo. Of note, treatment with ranolazine also
appeared to have some antiar-rhythmic properties, reducing events seen on ambulatory
monitoring. While these results demonstrate that ranolazine does not reduce clinical events, they
do suggest that ranolazine appears to be safe and effective when used as long-term antianginal
therapy, and that it may have some antiarrhythmic effects. Further studies are required to
examine the future of ranolazine as an antiarrhythmic agent.24
Nonpharmacologic Management
Although aggressive medical management and invasive intervention are indicated to treat CSA,
significant lifestyle modifications should also be encouraged to avoid MI and worsening of
disease. Many such interventions revolve around controlling known risk factors for cardiovascular
disease and include smoking cessation, increasing physical activity, and involvement in a weight-
management program to reduce obesity. Beyond these basic lifestyle modifications, several
nonpharmacologic strategies aimed at the improvement of angina symptoms are available,
including exercise training, surgical revascularization, enhanced external counterpulsation
(EECP), and surgical laser transmyocardial revascularization (TMR).
Exercise training or cardiac rehabilitation has shown remarkable efficacy in increasing exercise
tolerance,26,27 with more limited data showing improvement in symptomatology.26,28 Several studies
have also shown decreases in objective measures of ischemia, such as ST-segment depression
and myocardial perfusion imaging.26,28
While there are only limited data linking exercise programs to improvement in disease
progression and patho-physiology, exercise programs likely benefit the patient, and many
practitioners believe that these programs also entitle the patient to an improved sense of well-
being. In addition, exercise has been positively associated with improved control of known
cardiovascular risk factors such as hypertension, hyperlipidemia, and diabetes, and thus should
be enthusiastically recommended to all patients with CSA.
Several alternative nonpharmacologic methods for relieving angina are also recommended by
ACC/AHA guidelines, although primarily for refractory disease.5 EECP is a technique using cuffs
to compress a patient’s lower extremities during diastole, thereby forcing vascular
counterpulsation and increasing coronary artery blood flow. This procedure has been evaluated in
a placebo-controlled trial in which patients were randomized to receive EECP (35 hours) versus
inactive EECP over a four- to seven-week period. The results of the study demonstrated that
EECP reduced angina frequency and increased exercise time when compared with placebo.30
EECP has also been analyzed in the International EECP Patient Registry in comparison with
patients undergoing surgical revascularization (i.e., PCI or CABG), showing decreased frequency
of angina, MI, and hospitalizations at six months.31
TMR is an advanced surgical technique for patients with refractory angina. It can be performed
percutaneously or via surgical creation of transmural endomyocardial channels designed to
improve myocardial circulation. In general, these techniques have been shown to offer short-term
relief of angina symptoms, but few data exist describing long-term outcomes of the procedures.32,33
Conclusion
According to the ACC/AHA updated guidelines for the management of adult patients with CSA,
the central treatments continue to include beta-blockers, calcium channel blockers, and nitrates.
However, since the release of these guidelines in 2002, ranolazine has received FDA approval as
another potential treatment option in patients not receiving adequate control of anginal symptoms
on standard therapy, although it is not currently considered a first-line treatment option.
Several factors should be considered when selecting therapy for a patient newly diagnosed with
stable angina, including other comorbid conditions, concurrent medication use, and the cost of
therapy. Ranolazine is currently only available as a brand name product; therefore, monotherapy
may be significantly more expensive than combination therapy with generic options from the other
therapeutic classes (i.e., beta-blockers, calcium channel blockers, and nitrates). In terms of
improvement of anginal symptomatology, few data purport superiority of one medication over
another. However, given the fact that angina suggests active CAD and increased risk of MI, beta-
blockers should be considered the monotherapeutic treatment of choice. Other agents may be
considered in lieu of, or in combination with, beta-blockers, but offer no survival advantage.
Nonpharmacologic therapies remain a cornerstone in the treatment of CSA. While PCI is likely
the overall treatment of choice for uncomplicated coronary disease, there is no survival benefit
offered to patients receiving the procedure. Advanced therapies are available for refractory
disease, but few long-term data exist. Overall, aggressive pharmacotherapeutic management of
the patient with CSA remains critically important for first-line stabilization of CAD.
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