pain relief. How should E.R. be educated regarding the use of ibuprofen and aspirin concomitantly?
In 2006, the FDA released a warning statement on the concomitant use of both
aspirin and ibuprofen. The impetus for the statement was the growing recognition that
nonsteroidal antiinflammatory drugs (NSAIDs), in particular ibuprofen, may attenuate
the antiplatelet effects of low-dose aspirin. This FDA warning was then followed by
an updated scientific statement, from the AHA.
92 The mechanism of this interaction is
that both aspirin and nonselective NSAIDs bind to the same acetylation sites of the
cyclooxygenase enzyme. Although aspirin does this in a nonreversible fashion,
binding by an NSAID occurs in a reversible fashion. If an NSAID, such as ibuprofen,
is present, aspirin will be unable to bind to its site of action, and will be rapidly
cleared from the plasma. The result is the patient will not receive the antiplatelet
E.R. should be counseled on the consequences of the interaction between her
aspirin and ibuprofen. Additionally, if she can avoid or at least minimize (both dose
and duration) the use of ibuprofen, the effect on her cardiovascular health would be
optimized. If occasional use of ibuprofen cannot be avoided, it should be
administered to minimize the potential for interacting with her aspirin. This would
include taking ibuprofen at least 2 hours after her daily dose of aspirin, as well as
taking her daily aspirin dose at least 8 hours after the last dose of ibuprofen.
Although similar concerns exist for other nonselective NSAIDs (naproxen,
diclofenac), no formal recommendations exist on how to manage concomitant use of
92 Beyond the potential drug–drug interaction with aspirin
therapy, there has emerged a large body of observational evidence that the use of
NSAIDs in patients with underlying CVD may increase the risk of major adverse
cardiovascular events. Although the underlying mechanisms remain to be determined,
clinicians should minimize the use of NSAIDs if possible in patients with underlying
Percutaneous Coronary Intervention
PCI, also known as angioplasty, involves the percutaneous insertion of a balloon
catheter into the femoral or brachial artery. The catheter is advanced up the aorta and
into the coronary arteries at the coronary sinus. PCI initially involved the inflation of
a catheter-borne balloon that mechanically dilated a coronary artery obstruction
through arterial intimal disruption, plaque fissuring, and stretching of the arterial
wall. Balloon inflations were repeated until the plaque was compressed and
coronary blood flow resumed. Since then, alternative devices have been developed,
including rotational blades designed to remove atheromatous material, lasers to
ablate plaques, and intracoronary stents that are designed to maintain the patency of
the vessel after it is reopened.
94 Stents can be of the bare-metal (BMS) variety, or
contain a drug impregnated on the surface of the stent to prevent restenosis (DES). It
is estimated that more than 1,265,000 PCI procedures are performed in the United
States each year. An overwhelming majority of these procedures involve placement
of a BMS or DES (Fig. 12-5). PCI is indicated in patients with single-vessel or
multi-vessel disease and who are either symptomatic or asymptomatic.
Because of mechanical disruption of the atherosclerotic plaques and exposure of
plaque contents to the bloodstream during PCI, potent antiplatelet and antithrombotic
strategies are needed to prevent acute thrombotic events such as MI and death.
Current strategies in patients undergoing elective PCI involve the administration of
aspirin, a P2Y12 antagonist (clopidogrel, prasugrel, or ticagrelor), an antithrombin
agent, and occasionally a glycoprotein (GP) IIb/IIIa receptor antagonist in selected
patients. Although ticagrelor and prasugrel represent alternatives to clopidogrel in
patients undergoing PCI, current ACC/AHA guidelines recommend their use only in
patients undergoing PCI in the setting of ACS. In patients not taking aspirin on a daily
basis, 300 to 325 mg of aspirin should be given at least 2 hours before the procedure.
Patients currently on daily aspirin therapy should receive 75 to 325 mg of aspirin
before PCI is performed. A 600-mg loading dose of clopidogrel on or before the time
of the procedure is currently recommended, producing an antiplatelet action within 2
should be used in patients having elective PCI.
(See Chapter 13, Acute Coronary
Syndrome, for more information.)
expanded stent in position. (Illustration by Neil O. Hardy, Westpoint, CT.)
CASE 12-3, QUESTION 4: E.R. undergoes PCI plus placement of a DES to address a 75% lesion in her
The overall success of any procedure is directly related to the experience of the
operator, patient factors (such as LV function or number of vessels treated), and the
equipment used. In patients receiving balloon angioplasty alone (without stent
placement), repeat revascularization procedures (either repeat angioplasty or
surgery) may be required in as many as 32% to 40% of cases because of lesion
recurrence at the angioplasty site. The process is known as restenosis.
pharmacologic strategies have been studied in an attempt to reduce the risk of
restenosis. The outcome with most methods has been disappointing. The only strategy
that has been associated with a decrease in restenosis is the use of intraluminal
94 Stents are essentially metal scaffolding devices placed into the vessel after
balloon inflation has taken place. They provide a physical barrier to the recurrence
of a significant stenosis at the site. One of the early drawbacks of the use of stents
was the need for complicated antithrombotic regimens, including aspirin, heparin,
dipyridamole, and warfarin, to prevent in-stent thrombosis. DAPT—a combination of
a P2Y12 antagonist and aspirin—is effective at reducing in-stent thrombosis and is
now recommended for use after stent placement.
20,95 The duration of DAPT will
depend on the type of stent used, as well as other clinical characteristics of the
Recently, stents that elude antiproliferative agents such as sirolimus, paclitaxel,
zotarlimus, or everolimus have been shown in clinical trials to reduce the incidence
of restenosis compared with BMS.
96 Restenosis rates in clinical trials with these
DES were in the single-digit range, as compared to 15% to 20% with traditional
BMS. Soon after their introduction to the US market, DES use grew to the point that
greater than 90% of stent use was DES. This trend abruptly halted in the fall of 2006
when several reports indicated a higher than expected incidence of stent thrombosis a
year or more after DES placement. Although late stent thrombosis had previously
been reported with BMS usage, the incidence was rare.
20 Shortly after these initial
reports, an explosion of scientific literature emerged on the topic. Delayed
endothelialization is seen with DES compared with BMS. After placement of an
intracoronary stent, a healing process typically occurs resulting in growth of a
protective layer of endothelial cells over the stent surface, removing the stent surface
from blood exposure and drastically reducing the stimulus for thrombosis. In the case
of DES coated with paclitaxel, sirolimus, or everolimus, cellular growth may be
inhibited, significantly impairing endothelialization of the stent surface. In a small
number of patients, endothelialization does not seem to occur at all. In this scenario,
the stent structure remains continually exposed to flowing blood and is a potent
97 Because of the concerns of late stent thrombosis, the usage
of DES has decreased. Some use of DES is likely to continue, however, owing to the
tangible benefits in reduction of revascularization procedures in some patients.
Therefore, practitioners will need to continue to stay abreast of evolving information
regarding appropriate strategies to prevent late stent thrombosis.
One critical issue that has been identified as a cause of late stent thrombosis with
DES is the premature discontinuation of DAPT. As such, consideration of whether
the patient is likely to comply with aspirin and P2Y12 antagonist therapy, or afford
such therapy based on insurance status, has become a significant factor in the
decision process between using a BMS or DES. Previous recommendations called
for varying durations of combined therapy, depending on the type of stent used.
Because of the recognition of a delayed healing response to DES, current guidelines
recommend at least 1 year of DAPT in patients receiving a DES if patients are not at
an elevated risk of bleeding. For BMS placement, DAPT should continue for a
minimum of 1 month, and up to 1 year ideally, but this extended duration is not as
critical as it is in the setting of DES placement. After PCI, it is reasonable to use
aspirin 81 mg daily rather than higher doses.
20 The dose of clopidogrel should be 75
a better option for E.R. than PCI and stent placement?
Coronary artery bypass grafting is a complicated surgical procedure during which
an atherosclerotic vessel is bypassed using either a patient’s saphenous vein or
internal mammary artery (IMA; Fig. 12-6). The graft (i.e., the saphenous vein or
IMA) then allows blood to flow past the obstruction in the native vessel. The goals
of antianginal therapy, whether medical (pharmacologic) or revascularization, remain
unchanged: (a) to prolong life, (b) to prevent MI, and (c) to improve the quality of
The outcomes of medical therapy, PCI, and revascularization with CABG have
been compared, and current guidelines are available.
medical treatment in patients who would not be considered high risk, PCI in general
offers no improvement in the long-term incidence of MI or cardiovascular death, but
significantly reduces symptoms.
1 Because of her escalating symptoms on triple drug
therapy, the choice of PCI for E.R. is justified.
Medical Terminology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.)
Certain high-risk patient subgroups clearly have an improved outcome with
CABG. These include (a) patients with significant left main coronary disease; (b)
patients who have three-vessel disease, especially with LV dysfunction; (c) patients
with two-vessel disease with a significant proximal LAD lesion; (d) patients who
have survived sudden cardiac death; and (e) patients who are refractory to medical
treatment. In patients who do not meet these criteria, either medical treatment or PCI
1,20 Because E.R. does not fall into one of these categories, PCI is
preferable owing to the less invasive nature of the procedure and the equivalent
outcomes that are seen. These results were recently confirmed in the Clinical
Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE)
43 Patients with CAD were randomly assigned to aggressive medical treatment
with optimization of medical therapy and risk factors, or aggressive medical
treatment plus PCI. During a 4.6-year period, no significant difference was noted
between the groups in cardiovascular outcomes (death, MI, stroke, hospitalization for
ACS). The only difference noted was better control of anginal symptoms early on
with PCI, but that difference was no longer significant at the end of the study. These
results highlight the crucial role of optimizing medical therapy (including diet,
lifestyle changes, risk factor modification) for patients with CAD, regardless of
whether revascularization is performed.
CASE 12-3, QUESTION 6: E.R. undergoes PCI plus stent placement and returns to your pharmacy to have
Clopidogrel, a thienopyridine, inhibits platelet function as a noncompetitive
antagonist of the P2Y12 platelet adenosine diphosphate receptor. Clopidogrel is
dosed at 75 mg daily, and this dose has been demonstrated to be effective and safe as
monotherapy, or as a component of DAPT with aspirin, in a wide variety of settings
98 Despite proven efficacy, patients continue to experience
clinical events while receiving clopidogrel.
It is now understood that clopidogrel
does not produce a consistent antiplatelet response in many patients.
Although the term clopidogrel resistance was first used to describe patients who
do not have the expected antiplatelet response to standard doses of clopidogrel, a
better term to describe this phenomenon is clopidogrel nonresponsiveness.
Alternatively, the phrase high on-treatment platelet reactivity is also used commonly
in the literature, especially when characterizing the clinical consequences of
decreased antiplatelet response.
100 The presence of high on-treatment platelet
reactivity in patients who have undergone PCI has been linked to a higher rate of
stent thrombosis, MI, repeat revascularization, and death. This link has been
observed in both stable CAD patients undergoing elective PCI, and patients with
ACS. Although nonresponsiveness identifies an elevated risk for ischemic events, not
all patients with identified clopidogrel nonresponsiveness necessarily go on to have
There is a lack of consistency of how clopidogrel nonresponsiveness is defined. It
may be defined as the presence of a recurrent ischemic event while on therapy. But,
thrombosis is a complex interplay of many different factors and recurrent clinical
events do not necessarily imply a lack of antiplatelet effect. The identification of a
lack of the expected biologic effect on platelet function is a more appropriate
definition to work with. However, there are multiple tests available to assess the
antiplatelet activity of clopidogrel (and other antiplatelet agents), and it is unclear
which assay correlates best with clinical outcome and would be preferred to assess
clopidogrel nonresponsiveness. Because of the variability in available platelet
function tests, as well as definitions of nonresponsiveness, estimates for the
incidence of clopidogrel nonresponsiveness range anywhere from 5% to 44%.
Table 12-8 lists some of the available laboratory testing modalities for antiplatelet
Potential reasons for clopidogrel nonresponsiveness are multifactorial. One source
of nonresponsiveness is in the decreased biotransformation of clopidogrel from its
prodrug form to its active metabolite. Biotransformation is a multistep process
through the cytochrome P-450 system, but the most important enzyme is CYP2C19,
which exhibits variable metabolic capacity. Patients with the *1/*1 CYP2C19 alleles
are considered extensive metabolizers and are capable of generating sufficient levels
of clopidogrel’s active metabolite. Patients with one or two copies of either the *2 or
*3 alleles (considered loss of function alleles) are considered either intermediate or
poor metabolizers, generate lower amounts of active metabolite, and generally
produce a reduced antiplatelet effect as measured with available platelet function
102 Conversely, patients with one or two copies of the *17 allele (considered a
gain of function allele) are considered ultrarapid metabolizers and demonstrate a
heightened antiplatelet response with clopidogrel. With the unraveling of
pharmacogenomic factors related to clopidogrel response, a great deal of attention
has been given to the idea of identifying patients with copies of either the *2 or *3
allele and adjusting antiplatelet therapy accordingly. The FDA added language to the
clopidogrel package insert specifying that poor metabolizers have a higher
cardiovascular event rate, and that tests are available to identify who those patients
103 Although the presence of either loss of function allele
has been associated with an increased risk of clinical outcomes in some trials, this
finding has not been uniformly observed. Additionally, there are no prospective trials
evaluating a strategy of genetic testing with subsequent therapy changes. As such,
genetic testing related to clopidogrel therapy is considered to be in the
Commonly Used Platelet Function Tests for Assessment of Antiplatelet
Test Pros Cons Monitoring Key Points
Historical gold standard Large blood volume
VASP phosphorylation Whole blood assay
VerifyNow True point-of-care assay
Thromboelastography Whole blood assay
An alternative approach to address the issue of clopidogrel nonresponsiveness is
to assess platelet function in patients receiving clopidogrel. To date, trials conducted
have indicated that increasing loading or maintenance doses of clopidogrel do have
the potential to convert patients deemed nonresponders to responders.
not all patients can be converted and no trial has demonstrated that such an approach
leads to improved clinical outcomes.
105 Additionally, data indicate no improvements
in clinical outcomes from platelet function monitoring.
Empirically using higher doses of clopidogrel in all patients undergoing PCI is an
additional approach that has been considered in addressing clopidogrel
nonresponsiveness. Although no trials have been conducted in the elective PCI
setting, the CURRENT-OASIS 7 trial randomly assigned more than 25,000 ACS
patients to either standard dosing of clopidogrel (300 mg load, then 75 mg daily) or a
higher dosing regimen (600 mg load, then 150 mg daily for 7 days, then 75 mg
107 Patients were also randomly assigned to either high-dose (300–325 mg
daily) or low-dose (75–100 mg daily) aspirin. Approximately 17,000 of the 25,000
patients underwent PCI. Results showed that in PCI patients, the higher dosing
regimen of clopidogrel reduced the risk of MI at the cost of a higher incidence of
Although the results of the CURRENT-OASIS 7 trial might be viewed in a
positive light in relation to the prescription E.R. is presenting with today in your
pharmacy, an important caveat is that the CURRENT-OASIS 7 trial was conducted in
ACS patients, and it is unclear if the same benefits (and risks) can be expected in
patients undergoing elective PCI for symptom management of chronic stable angina.
been having some problems with heartburn lately and asks where she can find some over-the-counter
omeprazole. Is omeprazole appropriate to use in a patient with clopidogrel therapy?
Another source of variable clopidogrel response is through potential drug–drug
interactions involving the CYP2C19 enzyme. One class of agents that has generated
substantial controversy in this area are the proton-pump inhibitors (PPIs), given the
likelihood of coadministration to prevent GI bleeding as a result of antiplatelet
therapy. Several studies indicate there is a pharmacokinetic interaction between
PPIs, in particular omeprazole, with clopidogrel resulting in reduced levels of the
active metabolite. Evidence that this interaction is clinically significant is variable.
Several retrospective analyses suggest an increased risk for CVD events in patients
taking PPIs with clopidogrel therapy.
108–112 However, the available evidence from
randomized controlled trials does not support an increased clinical risk with this
112–114 However, one study has identified that PPI use alone is associated
with an elevated risk of CVD events.
115 Clinicians are faced with addressing this
issue from a medical–legal aspect as the FDA has incorporated language into the
clopidogrel package insert warning against the concomitant administration of
omeprazole and esomeprazole with clopidogrel.
116 The recommendation applies to
omeprazole and esomeprazole but not other PPIs. There is some evidence to suggest
that alternative PPIs such as pantoprazole have a lower propensity to inhibit
CYP2C19 and interact with clopidogrel. Until further information becomes
available, clinicians should first validate the need for PPI therapy in clopidogrel
patients. If acid suppressive therapy is needed, the use of a H2 antagonist (excluding
cimetidine which can inhibit CYP enzymes) or a PPI less likely to interact with
clopidogrel would seem to be appropriate options to consider.
VARIANT ANGINA (CORONARY ARTERY
electrolytes, chemistry panel, and cardiac enzymes are all within normal limits.
test without complication or evidence of CAD.
every day at 11 PM and NTG lingualspray 0.4 mg as needed for chest pain.
Is A.P.’s presentation typical for Prinzmetal variant angina?
A.P. presents with a classic picture of variant (Prinzmetal) angina, with transient
total occlusion of a large epicardial coronary artery as a result of severe segmental
spasm. Clinical manifestations include chest pain occurring at rest, often in the
morning hours. As with A.P., patients with Prinzmetal variant angina generally are
younger than patients with chronic stable angina and do not carry a high-risk profile.
Other vasospastic disorders, such as migraine attacks or Raynaud’s phenomenon,
may be present; smoking and alcohol ingestion can be important contributing
The hallmark of variant angina is ST-segment elevation on the ECG, which
denotes rapid and complete occlusion of the coronary artery. Many patients also have
asymptomatic episodes of ST-segment elevation. Transient arrhythmias and
conduction disturbances may be observed during pain, depending on the severity of
As documented by angiography, A.P. has vasospasm of the large RCA. This
transient, reversible narrowing is probably caused by increased coronary vascular
resistance. It can occur in the absence of atherosclerosis, as illustrated by A.P., and
also in the presence of CAD. One possible explanation for vasospasm occurring
more commonly at night or during the early morning hours is increased vasomotor
tone secondary to diurnal variations in catecholamines.
CASE 12-4, QUESTION 2: Oral amlodipine 10 mg every day was ordered for A.P. Would long-acting
another for treatment of Prinzmetal variant angina?
Because of their antispasmodic effects and low incidence of side effects, CCBs
are generally selected over nitrates or β-blockers for nocturnal vasospastic angina.
All CCBs appear equally effective in preventing Prinzmetal variant angina.
Intrinsically long-acting or sustained-release forms are preferred, however, and some
patients may respond better to one agent than to another.
In patients who continue to experience pain using maximal CCB doses,
combination therapy with a nitrate should be tried. Nitrates cause vasodilation by a
different mechanism than CCBs and are effective in treating Prinzmetal variant
118 To avoid tolerance, the nitrate-free interval for A.P. should be scheduled
during the day so that the early morning hours when vasospasm occurs are covered
by NTG. For example, A.P. could apply a transdermal NTG patch at bedtime and
remove it on awakening. Statin therapy is indicated for A.P.
-receptors that mediate vasodilation may allow unopposed α1
118 Therefore, a CCB or nitrate is
CASE 12-4, QUESTION 3: Will A.P. require treatment for the remainder of her life?
During the first year of therapy, up to 50% of patients experience spontaneous
remission by an unknown mechanism.
118 This occurs most often in patients who have
had a short duration of symptoms or who have normal or mildly diseased coronary
arteries (i.e., isolated vasospasm without atherosclerosis). If A.P. is pain free and
not experiencing significant arrhythmias or silent ischemic episodes of Prinzmetal
angina after 1 year, amlodipine could be tapered and discontinued. It is also
possible, however, that she will require treatment indefinitely. Modification of
smoking and ethanol ingestion may promote remission of Prinzmetal angina.
Cardiac syndrome X is a syndrome of angina or angina-like chest pain in the
setting of a normal coronary arteriogram, and ST-segment depression during
exercise. Several theories exist regarding the mechanism of pain production,
including microvascular dysfunction producing ischemia or chest discomfort without
ischemia in patients who may have an abnormal perception of pain. Half of patients
with cardiac syndrome X present with chest pain induced by exercise followed by 15
to 20 minutes of chest discomfort.
By symptoms alone, K.G.’s presentation does not significantly differ from that of a
patient with exercise-induced angina secondary to atherosclerosis. Of concern is the
finding of a 3-mm ST-segment depression on K.G.’s ECG, which raises concern of
severe CAD. The negative findings from her cardiac catheterization, however, rule
against both CAD and coronary artery spasm as a cause of her symptoms, and help to
confirm the diagnosis of cardiac syndrome X.
Treatment with a nitrate, CCB, or β-blocker all appear to offer some relief, but
overall the response to therapy in these patients is poor. The choice of agent will
likely depend on specific patient characteristics. Sublingual NTG is often ineffective
at treating acute attacks, although it should still be prescribed. Often a combination of
anti-ischemic therapy, analgesic therapy, and lifestyle modifications is necessary.
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