Download ISCHEMIC HEART DISEASE: CHRONIC STABLE ANGINA

18-1
ISCHEMIC HEART DISEASE:
CHRONIC STABLE ANGINA
An Uphill Battle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level III
Dane L. Shiltz, PharmD, BCPS
TuTran T. Nguyen, PharmD, BCPS
CASE SUMMARY
A 72-year-old man with known coronary artery disease (CAD) and
recent episodes of occasional light-headedness presents to the clinic
with refractory angina despite recent modifications in drug therapy.
His recent history of hemodynamic instability and light-headedness
must be considered when optimizing antianginal medications. Risk
factor modification is also necessary, requiring careful consideration of his dyslipidemia and use of a COX-2 inhibitor. The addition
of ranolazine introduces several considerations related to patient
selection and drug interactions.
QUESTIONS
Problem Identification
1.a. What drug-related problems appear to be present in this
patient?
• Angina pectoris, poorly controlled on current drug therapy
• Dyslipidemia, not on optimal pharmacological therapy
• Important risk-to-benefit consideration regarding COX-2
inhibitor therapy
1.b.Could any of these problems potentially be caused or exacerbated by his current therapy?
• Medical management of angina must take into consideration
the patient’s hemodynamic status. Although both diltiazem
and carvedilol are reasonable antianginal drugs, they are likely
the cause of his relatively low heart rate and blood pressure and
associated light-headedness. According to the 2012 guideline
for the management of patients with stable ischemic heart disease (IHD), β-blockers and calcium channel blockers (CCBs),
each alone or in combination, constitute medical therapy for
relief of symptoms for chronic stable angina (CSA).1 However,
combining nondihydropyridines (diltiazem or verapamil)
with β-blockers should be avoided due to the notable risk for
slowing atrioventricular nodal conduction, heart rate, and/or
cardiac contractility.1 Both classes reduce angina episodes,
increase exercise duration, and reduce acute sublingual nitroglycerin (NTG) use.1 The patient’s isosorbide mononitrate
(ISMN), an alternative agent for symptom relief that does not
reduce heart rate, is commonly associated with hypotension
especially at his higher dosage.
• According to a statement by the American Heart Association
(AHA), selective COX-2 inhibitors such as celecoxib increase
the risk of myocardial infarction (MI), stroke, heart failure, and
hypertension. This warrants careful consideration of the risks
associated with treatment against the benefit of symptom relief.
• Reduce symptoms of chest pain.
• Improve exercise tolerance.
• Slow progression of coronary atherosclerosis.
• Prevent recurrent cardiac events.
Therapeutic Alternatives
3.a.Does this patient possess any modifiable risk factors for
IHD?
• Clinical atherosclerotic cardiovascular disease (ASCVD) is
defined by the American College of Cardiology (ACC) and
the AHA as acute coronary syndromes (ACS), a history of MI,
stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral
arterial disease presumed to be of atherosclerotic origin. Jack
Palmer meets criteria for clinical ASCVD and is considered
to be at high-risk for cardiovascular morbidity and mortality.
• Previously, the Adult Treatment Panel (ATP) III guidelines
for secondary prevention recommended the use of statin and
non-statin therapies to target a goal LDL of <70 mg/dL for
very high-risk patients. There are a number of discrepancies
between this recommendation and what is currently available
in the literature. First, literature supporting the titration of
lipid therapy to a specific LDL goal is lacking.1,2 Current evidence suggests that improvements in cardiovascular outcomes
are associated with the use of maximally tolerated statin therapy
and reductions in LDL from a patient’s baseline. Secondly, an
LDL goal of <70 mg/dL is difficult to achieve and frequently
leads to initiation of non-statin therapies.2 Further reductions
in LDL using non-statin based therapies have not been shown
to improve morbidity or mortality.1,2 On the contrary, the
combination of statin and non-statin therapies carry a higher
likelihood of adverse events. Therefore, the most recent 2013
ACC/AHA Guideline on the Treatment of Blood Cholesterol
to Reduce Atherosclerotic Cardiovascular Risk in Adults
(2013 ACC/AHA Blood Cholesterol Guidelines) recommends
against treatment to target a specific an LDL goal, even in
very high-risk patients. To optimize outcomes and minimize
adverse events, four statin benefit groups were derived.2
(See Table 18-1.) Those who met the inclusion criteria for these
groups are deemed most likely to benefit from statin therapy.
TABLE 18-1 Statin-Intensity Recommendations3
Statin Benefit
Groups3
1
2
3
4
Criteria for Inclusion
Individuals with clinical
ASCVD
Primary elevations of LDL-C
≥190 mg/dL
Individuals age 40–75 years
with diabetes and LDL-C
70–189 mg/dL (without
clinical ASCVD)
Individuals without clinical
ASCVD or diabetes
who are 40–75 years
of age with LDL-C
70–189 mg/dL
Statin Intensity
Recommendations
High-intensity*
High-intensity*
•• Estimated 10-year ASCVD
risk >7.5%: high-intensity*
•• Estimated 10-year
ASCVD risk 5–7.5%:
moderate-intensity*
•• Estimated 10-year ASCVD
risk >7.5%: high-intensity*
•• Estimated 10-year
ASCVD risk 5–7.5%:
moderate-intensity*
*If high- or moderate-intensity statins are not tolerated, use the maximum dose tolerated by
the individual.3
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Ischemic Heart Disease: Chronic Stable Angina
Alexander J. Ansara, PharmD, BCPS AQ-Cardiology
2.What are the goals of pharmacotherapy for IHD in this case?
CHAPTER 18
18
Desired Outcome
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SECTION 2
Cardiovascular Disorders
Individuals 21–75 years of age with clinical ASCVD should be
initiated on or up titrated to a high-intensity statin (to produce
an LDL reduction of ≥50% from baseline).2 Individuals in
whom a high-intensity statin is indicated but cannot be tolerated, should be initiated on the maximally tolerated dose. The
2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for
the management of patients with stable IHD also emphasizes
the importance of initiating at least a moderate-intensity statin
(for an LDL reduction of 30–50%) in patients with stable
angina.1 Initiation of a guideline-based lipid lowering therapy
is an important way to minimize risk of recurrent cardiac
events in this patient.
• This patient’s waist circumference is 43 inches and his body
mass index (BMI) is 28.5 kg/m2. Physical inactivity, waist
circumference, and BMI >30 kg/m2 are risk factors associated
with ischemic heart disease.1,2 The 2012 guideline for management of stable IHD urges individuals to achieve and maintain
a BMI between 18.5 and 24.9 kg/m2 and a waist circumference
<40 inches in men and <35 inches in women.1
• Hypertension is a risk factor for IHD. Lifestyle modification
and pharmacotherapy should be aimed at a blood pressure
goal of <140/90 mm Hg.1 A more stringent systolic blood
pressure (SBP) goal of <120 mm Hg may be reasonable for
some patients. The SPRINT Trial was a prospective trial that
randomized participants >50 years of age with hypertension
(without diabetes) and at high risk for cardiovascular events to
a SBP goal of either <140 mm Hg or <120 mm Hg.3 The trial
was stopped early due to significant reductions in composite
outcome of MI, ACS not resulting in MI, stroke, acute decompensated heart failure, or death from cardiovascular causes
in individuals randomized to a SBP goal of <120 mm Hg as
compared to the standard <140 mm Hg group (1.65% per year
vs 2.19% per year; hazard ratio with intensive treatment, 0.75;
95% confidence interval [CI], 0.64–0.89; P < 0.001). Death
from cardiovascular causes was also lower in individuals in
the <120 mm Hg group (0.25% per year vs 0.48% per year,
hazard ratio with the intensive treatment, 0.57; 95% confidence interval [CI], 0.38–0.85; P = 0.005). It is important to
note that patients randomized to a SBP goal of <120 mm Hg
also experienced significantly more hypotension, syncope, and
falls. Furthermore, only about 30% of patients in this trial were
>75 years of age. This patient’s low heart rate (50 bpm) and
low-normal blood pressure (105/68 mm Hg) is already causing him to experience symptoms of hypotension. A SBP goal
of <120 mm Hg may not be appropriate, unless the patient is
able to tolerate the lower goal. Finally, the patient’s risk for
falls and adverse events should also be weighed in the decisionmaking process.
• He is currently taking celecoxib for low back pain, which may
put him at risk for cardiovascular events. According to the
AHA, celecoxib increases risk of MI, stroke, heart failure, and
hypertension. Furthermore, a black box warning is included in
the Celebrex package insert to highlight this risk. The warning
states “Celebrex® may cause an increased risk of serious cardiovascular thrombotic events, MI, and stroke, which can be fatal.
All NSAIDS may have a similar risk. This risk may increase
with duration of use. Patients with cardiovascular disease or
risk factors for cardiovascular disease may be at greater risk.”
3.b.What pharmacotherapeutic options are available for treating this patient’s IHD? Discuss the agents in each class with
respect to their relative utility in his care.
Both the 2012 guideline for management of stable IHD and the
2011 AHA/ACCF guidelines on secondary prevention and risk
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
reduction therapy for coronary disease provide current, evidencebased input on CSA management.1,4
• Nitrates are useful as antianginals because of their ability to
dilate coronary and systemic vessels, leading to reductions
in preload and afterload. The options in this class differ significantly from each other only in their onset and duration of
activity. Products with rapid onset and short duration are most
useful in terminating acute attacks or preventing anticipated
acute attacks caused by exertion. Agents with longer durations of action must be used for long-term prophylaxis and are
often used in combination with β-blockers or CCBs to prevent
or reduce angina and increase exercise tolerance in symptomatic CAD. Regardless of the product used, all nitrates can
produce tolerance within as little as 12–24 hours. Generally, a
10–12-hour nitrate-free interval each day is recommended to
avoid the development of tolerance in long-term prophylaxis
regimens.5
✓NTG oral products are generally not used for prophylaxis.
NTG transdermal patches allow for once-daily application,
whereas NTG topical paste is typically applied three to four
times daily.
✓Isosorbide dinitrate (ISDN) oral products are typically given
two to three times daily when used prophylactically. Onset
of action ranges from 30 to 60 minutes with duration of
about 8 hours.
✓ISMN is available in two types of oral formulations: (a) a
tablet that must be taken orally in two divided doses 7 hours
apart (eg, Monoket and Ismo) and (b) an extended-release
tablet that may be taken once daily (eg, Imdur). Onset
of action for both ISMN formulations ranges from 30 to
60 minutes. Immediate-release ISMN lasts 12–14 hours;
extended-release lasts 12 hours.
All of these long-term prophylactic regimens are effective, but they differ with respect to convenience. This patient
is presently receiving ISMN 120 mg once daily. This product
is the most convenient way for patients to take nitrate therapy because of its extended-release formulation and inherent nitrate-free interval (duration of action is 12 hours). If
necessary, the dosage may be increased up to 240 mg per
day, but the incremental efficacy gained may be minimal.
• CCBs are useful in treating angina primarily because of their
ability to dilate systemic arterioles and coronary arteries, thus
reducing afterload and coronary vascular resistance. They are
grouped according to their chemistry into three major classes:
✓Benzothiazepines (diltiazem)
✓Phenylalkylamines (verapamil)
✓Dihydropyridines (amlodipine, isradipine, felodipine, nicardipine, nifedipine)
Verapamil and diltiazem also have the potential to reduce myocardial oxygen demand by reducing myocardial contractility and
heart rate. In the normal heart, reflex sympathetic stimulation effectively tempers reductions in contractility. In individuals unable to
mount an adequate sympathetic response to such stimulation, the
negative inotropic effects may become clinically apparent. We must
consider that this patient has a relatively low heart rate; therefore,
use of a negative inotrope such as diltiazem is inadvisable.
In contrast, the dihydropyridines are noted for clinically exerting
very little negative inotropic effect because of induction of a reflex
sympathetic response brought about by their marked systemic
vasodilatory capacity. The sympathetic response induced by dihydropyridines can also lead to tachycardia that can increase myocardial oxygen demand and worsen angina symptoms. However,
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There are numerous β-blockers available in the United States for
the treatment of heart disease. They are available as both cardioselective and nonselective agents.
✓Atenolol, metoprolol, and bisoprolol are examples of cardioselective β-blockers that are relatively specific for β1-receptors
in the heart, although this specificity is lost at higher doses.
✓Propranolol, nadolol, and timolol are nonselective agents that
antagonize both β1 and β2 receptors throughout the dose
range.
✓Carvedilol is a nonselective β-adrenergic blocking agent with
α1 blocking activity. The maximum dose is 25 mg BID if
weight is <85 kg and 50 mg BID if weight is >85 kg.
Because of their pharmacologic properties, β-blockers may be
contraindicated (either relatively or absolutely) in a variety of
conditions including reactive airway disease, diabetes mellitus, and
depression.
• Ranolazine (Ranexa) is an antianginal agent approved for the
treatment for chronic stable angina for use in combination with
amlodipine, β-blockers, or nitrates in patients who have not
achieved an adequate response with these agents. Ranolazine
• Ivabradine (Corlanor) is a novel heart rate-lowering agent that
inhibits cardiac pacemaker If channels within the sinoatrial
(SA) node. Due to its SA nodal effect, ivabradine should be
avoided in atrial fibrillation or any SA nodal dysfunction.
While its use for CSA remains off-label in the United States,
ivabradine is approved in Europe for symptomatic management of CSA in adults with CAD in normal sinus rhythm
who are either unable to tolerate or have a contraindication to
β-blockers. Ivabradine can also be combined with a β-blocker
in patients who continue to demonstrate CSA symptoms
despite an optimal β-blocker dose and maintain a heart rate
that is >60 bpm. Ivabradine provides additional anti-ischemic
effect when added to β-blockers, because it does not induce
β-blocker-attributed coronary alpha-adrenergic vasoconstriction. Furthermore, CCB-ineligible patients may alternatively
receive ivabradine or it may be combined with a CCB for
additional symptomatic benefit. For ivabradine combinations
with a CCB, a dihydropyridine CCB is preferred to avoid
bradycardia, the most common adverse effect of ivabradine.
Ivabradine demonstrates statistically significant symptomatic
benefit notably in stable CAD when the pretreatment baseline
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Ischemic Heart Disease: Chronic Stable Angina
• β-Blockers are useful antianginal drugs because of their ability
to inhibit the effects of catecholamines on the heart and blood
vessels. They reduce myocardial oxygen demand by reducing heart rate, contractility, and blood pressure. β-Blockers
have a good track record in ischemic disorders, particularly
in their ability to reduce severe recurrent angina, reduce risk
for recurrent MI, and improve survival in patients who have
suffered an MI. CCBs reduce severe angina frequency and
post-MI reinfarction rate similar to β-blockers, but they do
not improve the post-MI mortality rate. Both the current
stable CAD and secondary prevention guidelines1,4 offer a
Class I recommendation about using a β-blocker for 3 years
in all patients with normal LV function after MI or ACS but a
corresponding level of evidence derived from a single or multiple nonrandomized trials. Moreover, β-blocker use beyond
3 years in these populations is less supported, representing
only a Class IIa recommendation based on single or nonrandomized trials.1,4 Lastly, the Class IIb recommendation on
chronic β-blocker use in CAD patients without a history of MI
or ACS is supported by only case studies and/or expert opinion since no large trials have assessed effects of β-blockers on
coronary outcomes in CSA.1 An international, prospective,
observational registry evaluated β-blocker presence or absence
in three patient populations: any known prior MI, CAD without MI, and CAD risk factors only.6 The primary outcome was
a composite of cardiovascular death, nonfatal MI, or nonfatal
stroke. After a median follow-up of 43 months in each group,
results from 44,708 patients showed the following for the
primary end point: β-blocker 16.93% versus no β-blocker
18.60%, HR 0.90 (95% CI, 0.79–1.03), P = 0.14 in the prior
MI cohort; β-blocker 12.94% versus no β-blocker 13.55%, HR
0.92 (95% CI, 0.79–1.98), P = 0.31 in the CAD without MI
cohort; and β-blocker 14.22% versus no β-blocker 12.11%,
HR 1.18 (95% CI, 1.02–1.36), P = 0.02 in the risk factors for
CAD cohort. Consequently, this trial supports the existing
guidelines that patients with history of MI or diagnosed CAD
do not experience ongoing, improved outcomes beyond subjective symptomatic angina relief.
is a piperazine derivative and its mechanism of action is poorly
understood. It appears to produce its antianginal effect by
inhibiting ischemia-related late sodium entry into myocardial
cells and thereby inhibiting intracellular calcium overload. A
unique feature of ranolazine is that its mechanism is hemodynamically independent, leading to only minimal effects on
resting and exercise heart rate and blood pressure. This unique
feature may be of critical importance in our patient due to his
recent hemodynamic instability. Three pivotal trials, MARISA,
CARISA, and ERICA, demonstrated the ability of ranolazine
to significantly improve exercise duration and decrease angina
frequency and sublingual nitrate consumption.7 The MERLIN
TIMI-36 trial later supplied reassuring data on its safety and
efficacy in the stable angina. This trial was aimed at addressing whether ranolazine can reduce the combined end point of
cardiovascular death/MI/recurrent ischemia in 6,560 high-risk
patients with an ACS. Although there was no difference in the
primary end point in this trial, the antianginal effect and safety
of ranolazine was confirmed. Ranolazine decreased recurrent
ischemia by 13% (P = 0.03) without increasing symptomatic
documented arrhythmias versus placebo. It is generally well
tolerated, with constipation, nausea, dizziness, and headache
being the most common adverse events reported. Because
ranolazine prolongs the QT interval (6 milliseconds at peak
plasma concentration), it was initially approved as a backup
agent for patients who had not achieved an adequate response
with other antianginal drugs. However, in November 2008,
ranolazine gained FDA approval for use as a first-line agent
in chronic angina based on the MERLIN TIMI-36 results.
The current labeling also states that the drug reduces the risk
of ventricular arrhythmias, new-onset atrial fibrillation, and
bradycardia in patients with coronary disease and lowers levels
of glycosylated hemoglobin in patients with diabetes. Dosing
is initiated at 500 mg orally twice daily and can be titrated to
1,000 mg twice daily as needed based on clinical symptoms.
Ranolazine is extensively metabolized by CYP3A4 and
thereby subject to numerous drug interactions. For example,
it is contraindicated for use with strong CYP3A4 inhibitors
(eg, ketoconazole and clarithromycin) and CYP3A inducers
(eg, rifampin and phenobarbital). With moderate CYP3A
inhibitors (eg, diltiazem, verapamil, and erythromycin), the
ranolazine dose should be limited to 500 mg twice daily. There
are numerous other drug interactions as well.
CHAPTER 18
the preexisting use of a β-blocker would prevent this reflex effect.
Because amlodipine neither lowers heart rate nor reduces myocardial contractility, it is a reasonable option for this patient in a dose of
5–10 mg once daily, perhaps in lieu of diltiazem 240 mg once daily.
18-4
SECTION 2
heart rate ≥70 bpm. Ivabradine should be discontinued if atrial
fibrillation occurs, any SA node dysfunction develops, or heart
rate persistently remains <50 bpm despite dosage reduction.
Lastly, since this patient’s pretreatment heart rate of 50 bpm
is below the 60 bpm threshold required to initiate, he is not a
candidate for ivabradine.
Cardiovascular Disorders
• Antiplatelet therapy is another critical part of this patient’s
IHD regimen. The Antithrombotic Trialists’ Collaboration
Group published a meta-analysis of all randomized antiplatelet
trials in high-risk patients, including 287 studies (up to 1997)
and 135,000 patients.8 The study results demonstrated a 22%
overall odds reduction of serious vascular events (eg, nonfatal MI, nonfatal stroke, or vascular death) in patients taking
antiplatelet therapy compared with controls (10.7% vs 13.2%;
P < 0.001). The greatest benefit (30% odds reduction) was
achieved in patients with acute MI.
✓Aspirin exerts its antiplatelet effect by inhibiting thromboxane A2 production, one of several stimulators of platelet
aggregation. Aspirin monotherapy in a dose of 81–162 mg
daily is recommended as the initial antiplatelet agent of
choice for MI prevention in patients with IHD and no history of intracoronary stenting.
✓Clopidogrel (Plavix) is a thienopyridine derivative that serves
as a useful antithrombotic alternative to aspirin. It works by
inhibiting adenosine diphosphate-induced platelet aggregation. In the CAPRIE trial, clopidogrel was administered to
more than 19,000 patients with a history of atherosclerotic
vascular disease as evidenced by recent ischemic stroke, MI,
or symptomatic peripheral vascular disease.9 In a doubleblind, randomized fashion, patients received either aspirin
325 mg daily or clopidogrel 75 mg daily. After an average of
1.9 years of follow-up, there was a marginal but statistically
significant 8.7% relative risk reduction in the combined end
point of MI, ischemic stroke, or vascular death in favor of
clopidogrel.
Despite this slight superiority of clopidogrel over aspirin in
patients with ASCVD, the superiority of the composite end point
was driven by improved outcomes in patients with peripheral arterial disease. Rates of MI, however, were no different with ASA when
compared with clopidogrel (4.84% vs 5.03% per year, P = 0.06),
a finding that supports clopidogrel as an effective alternative to
aspirin therapy when necessary. The data with aspirin are robust
and cost of therapy is an important issue (aspirin is inexpensive compared with clopidogrel). Current guidelines recommend
clopidogrel 75 mg daily as an alternative in patients who cannot
take aspirin.1,4 This patient is taking an acceptable dose of aspirin,
although lowering the dose to an enteric-coated baby aspirin (81 mg
per day) could be considered to minimize the risk of gastrointestinal
bleed while maintaining an acceptable level of antiplatelet activity.
• ACE inhibitors are indicated in all patients with CAD who also
have diabetes, LV dysfunction, or chronic kidney disease and
should be utilized in patients at high risk for coronary events.10
The benefits of ACE inhibitor therapy in patients at high
risk for CV events are most evident in the Heart Outcomes
Prevention Evaluation (HOPE) trial. In this trial, patients
>55 years old with evidence of vascular disease or diabetes
plus one additional risk factor were randomized to treatment
with ramipril versus placebo and followed for an average of
4 years. Independent of effects on blood pressure, treatment
with ACE inhibitor therapy was overwhelmingly beneficial as
demonstrated by significant reductions in the rates of mortality, MI, stroke, revascularization, cardiac arrest, heart failure,
complications related to diabetes, and new onset of diabetes.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Treating 1,000 patients with ramipril for 4 years prevented
about 150 events in approximately 70 patients. There are
10 ACE inhibitors available in the United States and they are all
considered to be cardioprotective and renal-protective. Most
trials of ACE inhibitors in cardiovascular medicine have utilized aggressive dosing strategies, pushing doses to the mid- to
upper end of the dosing range. Our patient could benefit from
more aggressive dosing of his lisinopril, but we may potentially
be limited by his low blood pressure and light-headedness.
• Angiotensin receptor blockers (ARBs) are also indicated in
patients with CSA or multiple risk factors for a cardiovascular
event. The ONTARGET trial utilized similar inclusion criteria
to the HOPE trial and evaluated whether treatment with telmisartan 80 mg was comparable to treatment with ramipril 10 mg,
and whether the combination of both drugs provided additional
cardioprotective effects. A total of 25,620 patients were randomized and followed for >4.5 years. Treatment with telmisartan
was equal to treatment with ramipril in reducing rates of death,
MI, stroke, hospitalization for heart failure, and cardiac death.
The combination of telmisartan and ramipril offered no clinical
benefit but was associated with a higher incidence of adverse
effects, specifically hyperkalemia, hypotension, and renal failure.
In light of these findings, in addition to results from other trials,
ARBs appear to be an acceptable option for mortality reduction
and cardioprotection in patients at high risk for cardiac events
and are recommended in the 2012 guideline for management of
stable IHD for all patients intolerant to ACEIs.1
• Other considerations include risk factor management such as
achievement of ideal body weight, as well as optimization of
blood pressure and cholesterol lowering therapies, which will
simultaneously modulate cardiovascular risk factors for this
patient.
Optimal Plan
4.Given the patient information provided, construct a complete
pharmacotherapeutic plan for optimizing management of his
IHD.
• Currently, the main issues in this patient are refractory angina
(despite a recent increase in ISMN to 120 mg daily) and occasional light-headedness associated with relatively low heart rate
and blood pressure. Due to his bradycardia and low-normal
blood pressure, it is advisable to discontinue diltiazem and cautiously replace it with amlodipine 2.5 mg once daily, which will
provide equivalent antianginal effectiveness without lowering
heart rate or depressing contractility. The amlodipine may then
be titrated as tolerated for better angina control as his blood
pressure allows. Carvedilol is effective for angina and secondary
prevention of CAD. Ideally, the carvedilol could be titrated to
a maximum dose of 50 mg BID (since weight >85 kg), but his
current blood pressure and heart rate limit us in this regard.
Verapamil should be avoided since it slows cardiac conduction
and thus heart rate to a greater extent compared with diltiazem.
• Decrease aspirin to enteric-coated 81 mg once daily to minimize risk of GI bleed.
• Serious consideration should be given to discontinuing celecoxib in this patient due to the increased risk of cardiac events
associated with the use of selective COX-2 inhibitors. Alternative options exist for pain relief that do not carry the same
cardiac risks and the American Heart Association suggests a
stepwise approach. For musculoskeletal pain, nonpharmacologic approaches can be tried first including physical therapy,
exercise, weight loss, heat/cold therapy, and orthotics. If these
18-5
Moderate-Intensity
Statin Therapy (daily
dose lowers LDL on
average by 30–50%)
•• Atorvastatin 40–80 mg
•• Rosuvastatin 20–40 mg
•• Atorvastatin 10–20 mg
•• Rosuvastatin 5–10 mg
•• Simvastatin 20–40 mg
•• Pravastatin 40–80 mg
•• Lovastatin 40 mg
•• Fluvastatin XL 80 mg
•• Fluvastatin 40 mg bid
•• Pitavastatin 2–4 mg
Low-Intensity Statin
Therapy (daily dose
lowers LDL up to 30%)
•• Simvastatin 10 mg
•• Pravastatin 10–20 mg
•• Lovastatin 20 mg
•• Fluvastatin 20–40 mg
•• Pitavastatin 1 mg
measures are ineffective, intermittent or scheduled acetaminophen, aspirin, or short-term use of narcotic analgesics is recommended as a first-line drug. NSAIDs with the lowest COX-2
selectivity should be used next, followed by NSAIDs with some
COX-2 selectivity or, as a last resort, COX-2-selective NSAIDs.
If NSAIDs are required, they should be used in the lowest
effective doses for the shortest duration necessary.
• Risk factor modification is also necessary and is a major focus
of the 2012 guideline for management of stable IHD and the
2013 ACC/AHA Blood Cholesterol Guidelines. This patient
is presently taking a moderate-intensity statin (simvastatin
40 mg daily), and switching to a high-intensity statin (eg, atorvastatin 40 mg or rosuvastatin 20 mg) (see Table 18-2) would
be appropriate based on qualification for clinical ASCVD. In
doing so, and with the additional recommendations of AHA
diet, exercise, and weight loss, we will be addressing his risk
factors for cardiovascular events. Physical activity should
include 30–60 minutes of moderate-intensity aerobic activity, such as brisk walking, on at least 5 but preferably 7 days
of the week. Dietary therapy should include a reduced intake
of saturated fats (7% of total calories), transfats (<1%), and
cholesterol (<200 mg per day). Adding plant stanol/sterols
(2 g per day) may reduce LDL by up to 5–15%, and viscous
fiber (>10 g per day) serves as a reasonable option to further
lower LDL-C by up to 3–5%.1
Outcome Evaluation
5.When the patient returns to the clinic in 2 weeks for a follow-up
visit, how will you evaluate the response to his new antianginal
regimen for efficacy and adverse effects?
• Efficacy: Ask him about the number and severity of anginal
attacks and the provocative factors for attacks. If the attacks
remain, is the character and duration of attacks similar to
before? What distance can he walk before experiencing symptoms? Does sublingual NTG relieve the pain? How many SL
NTGs have been used per day or per week? Have any attacks
occurred at rest, which is a sign of unstable angina and would
require hospital admission?
• Adverse effects:
✓Check vital signs. His current heart rate and blood pressure
are relatively low and associated with light-headedness.
The conversion from diltiazem to amlodipine should have
allowed his heart rate to increase somewhat but hopefully
did not lower his blood pressure any further. Ask the patient
about symptoms of dizziness, light-headedness, headache,
and facial flushing. Check for the presence of edema, which
is the most common adverse effect of amlodipine.
Patient Education
6.What information will you communicate to the patient about
his antianginal regimen to help him experience the greatest
benefit and fewest adverse effects?
• General information: Keep all medicines in original containers to avoid confusing them, and keep them out of reach of
children. Do not stop any of your medicines abruptly without
talking to your physician. If you miss a dose of medicine, take
it as soon as you remember but not if it is approaching your
next schedule dose. Do not double doses. Consider using a pill
box to help ensure good compliance with medications. Keep
track of the number of chest pain episodes you experience
while using the new medicine. Keep track of how many NTG
tablets you use.
• Amlodipine: This medicine was prescribed to treat your angina
in place of diltiazem, which was a suboptimal medication
for you due to your weakened heart muscle and low heart
rate. Amlodipine works by expanding coronary arteries and
increasing coronary blood flow to relieve chest pain but does
not lower heart rate or depress heart function. Take a 10-mg
tablet by mouth once daily in the morning. This medicine may
cause flushing, dizziness, headache, or swelling in your ankles
and feet.
• ISMN extended-release tablets: This medicine is for prevention
of chest pain attacks. It works by increasing blood flow to your
heart. Take a 120-mg tablet once daily in the morning. Do not
break, crush, or chew it before swallowing. It is designed to last
for only 12 hours (while you are awake) so that you may have a
nitrate-free interval each day to prevent tolerance to the medication. This medicine can cause dizziness or light-headedness,
especially when getting up from a lying or sitting position. It
may also cause headache, rapid pulse, and flushing of the face
and neck. If you experience headaches from this medication,
you may take preventative acetaminophen for a few weeks
until your body develops tolerance to this long-acting nitrate.
• NTG sublingual tablets: This medicine should be used at the
start of an angina attack to relieve chest pain. You may also
use this medicine by taking it just before doing something that
you think will cause chest pain. Dissolve one tablet under the
tongue; do not swallow it. If necessary, additional tablets can be
taken every 5 minutes for a total of three tablets in 15 minutes.
If the pain persists, you should notify your physician or
call 911 immediately. Do not try to drive to the hospital. Keep
these tablets in their original container with the cap tightly
closed. Taking them out of the original container causes them
to break down faster. Store them away from excessive heat and
moisture. Replace these tablets every 6 months after the original container has been opened. This medicine has similar side
effects to ISMN, but they may be more obvious or more severe
because this medicine acts much more quickly than ISMN.
• Enteric-coated aspirin: Aspirin has been prescribed to help
prevent heart attack and stroke. You should take an 81-mg
tablet once daily with food as directed by your physician. You
should report stomach pain, black stools, or any easy bleeding
or bruising. Do not take ibuprofen before taking your aspirin
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Ischemic Heart Disease: Chronic Stable Angina
High-Intensity Statin
Therapy (daily dose
lowers LDL on average
by 50%)
✓Monitor for signs of muscle pain. Some patients may not
tolerate high-intensity statin therapy and may experience
myopathy and myositis. If he complains of abnormal muscle
pain, muscle weakness, muscle tenderness after initiation
of a high-intensity statin, switching to a moderate-intensity
statin is warranted.
CHAPTER 18
TABLE 18-2 Dosing by Statin Intensity3
18-6
SECTION 2
or it may cause your aspirin to be ineffective. If you need to
take ibuprofen, take it an hour after your aspirin dose.
Cardiovascular Disorders
• Carvedilol: This medicine is prescribed for multiple reasons—
to prevent episodes of chest pain and to lower your risk of a
recurrent heart attack and death from coronary artery disease.
It works by lowering your heart rate and blood pressure and
decreasing the workload of the heart. Take 6.25 mg twice daily
with food about 12 hours apart. This medicine may cause dizziness, drowsiness, and fatigue. If you check your blood pressure and pulse at home, please do so and bring the results with
you to your next appointment. Call your physician if your top
blood pressure number is <100 or if your pulse is 50 or less.
• Celecoxib: This medicine, and other NSAIDs, may increase
your risk of cardiac events such as heart attack and stroke.
We recommend that you stop taking Celebrex® and try physical therapy, exercise, weight loss, and/or heat/cold therapy
for your back pain. If this is ineffective, consider Tylenol®
500–1,000 mg every 6 hours as needed, not to exceed 4000 mg
in 24 hours.
• Ranolazine: This is a newly approved medication that, when
added to your other medicines, can relieve chest pain and
reduce the amount of sublingual NTG you require. It works
by a novel mechanism that will not further lower your blood
pressure or heart rate. Do not use this medicine to treat sudden
onset of chest pain. Take 500 mg twice daily about 12 hours
apart, with or without food. Do not crush, break, or chew this
medicine. If you miss a dose, take it as soon as possible; if you
are >6 hours late, skip the missed dose and return to your
regular schedule. Ranolazine interacts with a number of other
medicines and it is critical that you avoid new medicines until
you have discussed these with your physician or pharmacist.
Avoid grapefruit and grapefruit juice as well. This drug is
generally well tolerated. The most common adverse effects are
constipation, nausea, dizziness, and headache.
• Lisinopril: While this is not specifically being used to prevent
angina attacks, it is perhaps your most heart-protective medication and has been proven to reduce your likelihood of having
a heart attack or stroke, or dying from a heart problem. Take
this blood pressure medication once daily. Your physician
may occasionally check your blood tests to assess your kidney
function and potassium levels. While rare, this medication
can cause something called angioedema. Call 911 if you notice
swelling of your lips, tongue, or throat, or if you feel that you
are having trouble breathing.
• Statin: This medication decreases cholesterol, slows the development of plaque in your blood vessels, and prevents cardiovascular events. Take this medication once daily. This
medication may interact with other medications. Please speak
with your physician or pharmacist prior to initiating new
medications or supplements. Avoid grapefruit and grapefruit
juice while taking this medication. If you miss a dose of this
medication, take it as soon as your remember. If it is too close
to the next dose, skip the missed dose and resume your regular schedule. This medication may cause some muscle injury.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Signs and symptoms may include abnormal muscle pain, muscle weakness, muscle tenderness, changes in skin color over the
muscle that is affected, and red or brown colored urine. Muscle
pain can occur anywhere, but it commonly occurs in the lower
back or calf. Symptoms of muscle pain can develop at any time
during the course of therapy. However, the average time to
development of symptoms is roughly 6 months. If you experience any of the above symptoms, discontinue use of your statin
therapy and promptly seek medical attention.
■■ FOLLOW-UP QUESTION
1.What drug therapy changes would you recommend to avoid or
minimize drug interactions with ranolazine?
• St John’s wort is a strong CYP3A inducer and should be
avoided in combination with ranolazine, as it may decrease the
plasma concentration of ranolazine.
• Although plasma levels of some statins, including simvastatin
and atorvastatin (both CYP3A4 substrates), may increase
2-fold with ranolazine 1,000 mg BID, dose adjustments are
not recommended.
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