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132 PART III Coronary Artery Disease
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days after acute MI and followed for a mean of 25 months.
Overall mortality and adverse cardiac events were similar in the
diltiazem and placebo groups, but a significant interaction was
observed between diltiazem treatment and pulmonary congestion
(detected radiographically) or LV systolic dysfunction (EF <
40%). Among the more than 75% of trial participants without
pulmonary congestion, diltiazem conferred benefit with a significant (23%) reduction in adverse cardiac events; in the nearly
20% of patients with pulmonary congestion or LV dysfunction,
diltiazem was associated with a significant (41%) increase in
adverse cardiac events.
150
A meta-analysis of the trials indicated that CCBs did not reduce
mortality or morbidity in acute MI.
151
The main side effects of
CCBs are hypotension, bradycardia, AV block, and worsening
CHF. Potential risk to the fetus requires caution in pregnant
patients.
Recommendations
In aggregate, these results suggest that, while the nondihydropyridine CCBs verapamil and diltiazem may be beneficial after acute
MI for patients with no signs of CHF and preserved LV systolic
function, they should be avoided for any patient with CHF or LV
systolic dysfunction. Even among patients with preserved EF after
AMI, the weight of evidence favors long-term use of β-blockers
for all patients without contraindications, which should not be
limited by prior use of CCBs. The nondihydropyridine CCBs, such
as verapamil and diltiazem, may be useful for heart rate control
for tachyarrhythmias when β-blocker therapy is contraindicated
or ineffective. Verapamil, diltiazem, and amlodipine can be useful
for treatment of angina or hypertension in select patients after
STEMI when β-blockers (and/or nitrates) are ineffective, not
tolerated, or contraindicated and in whom there are no serious
contraindications. Routine use of CCBs in patients with STEMI,
however, is not recommended (see the Appendix).
ANTIDYSRHYTHMIC THERAPY
Cardiac arrhythmias are common after STEMI both before and
after reperfusion. Most episodes of ventricular fibrillation (VF)
and ventricular tachycardia (VT) occur in the first 48 hours. As
many as 10% of patients receiving fibrinolytic therapy in the
GUSTO-I trial had sustained ventricular arrhythmias complicating their hospital course.
in early MI, a routine therapy in the prefibrinolytic era, is no
longer recommended and, in general, antidysrhythmic drugs
should be used with great caution in patients with acute MI.
In the GUSTO-I and GUSTO-IIb trials, the prophylactic use of
lidocaine in STEMI patients showed no mortality benefit.
meta-analysis of lidocaine use in 14 trials found a 33% reduction
in the risk of primary VF, but no mortality benefit and an increased
risk of bradycardia and fatal asystole.
The Cardiac Arrhythmia Suppression Trial (CAST)
double-blind, randomized, controlled study designed to test the
hypothesis that suppression of frequent premature ventricular
complexes (PVC) with class I antidysrhythmic agents after acute
MI would reduce mortality. In CAST, patients randomly assigned
to receive the class I antidysrhythmic drugs (encainide, flecainide,
152
The prophylactic use of lidocaine
154
155
was a
153
A
and moricizine) showed effective suppression of the PVCs and
nonsustained VT, but had worse outcomes; mortality was significantly greater among patients prescribed encainide and
flecainide than patients given placebo. The results of CAST
dramatically altered management of ventricular ectopy following
acute MI; use of class I antidysrhythmic drugs in that setting is
generally avoided.
Recommendations
A conservative approach to arrhythmia management is recommended, with close monitoring during the early post-MI period.
Evidence that intravenous β-blockers decrease early VF
156
supports
the routine early use of β-blockers for patients with or showing
high risk for VT or VF. For significant ventricular arrhythmias,
the use of intravenous amiodarone and lidocaine may be considered, in accordance with the Adult Advanced Cardiovascular
Life Support 2015 American Heart Association Guidelines
Update for Cardiopulmonary Resuscitation and Emergency
Cardiovascular Care.
157
The ACC/AHA guidelines of ventricular arrhythmia management in STEMI are summarized in the
Appendix.
MORPHINE AND OTHER ANALGESIC AGENTS
Pain relief is an important aspect of the early management of
acute MI; morphine sulfate is the analgesic of choice for managing
pain in these patients. Morphine binds to central nervous system
receptors, preventing them from transmitting pain signals to
the brain. In acute MI, morphine has analgesic, anxiolytic, and
hemodynamic properties. It relieves pain that contributes to
the hyperadrenergic state, decreases blood pressure via arterial
dilation and venodilation, decreases heart rate via increased vagal
tone and withdrawal of sympathetic tone, decreases myocardial
oxygen demand, and relieves pulmonary edema. A dose of 1
to 4 mg intravenously, repeated at 5- to 15-minute intervals, is
commonly used.
The most common side effects of morphine are nausea and
vomiting, presenting in 20% of patients. Adverse effects include
hypotension, especially prominent in patients who are volume
depleted, have been given vasodilator therapy, or have infarction
of the right ventricle. Treatment of morphine-induced hypotension includes placing the patient in a supine or Trendelenburg
position and administering intravenous saline boluses, with
the addition of atropine (0.5 to 1.5 mg intravenously) for
concomitant bradycardia. Rarely, the narcotic antidote naloxone (0.4 to 2 mg intravenously) or an inotropic agent may be
needed. Respiratory compromise from morphine overdose can
be treated with naloxone and, very rarely, may require intubation
for respiratory support. Other narcotics should be considered
in patients with severe side effects or allergic reactions to
morphine.
It is noteworthy that an observational study reported increased
mortality in NSTE ACS patients treated with morphine,
led the ACC/AHA to downgrade its recommendation from class
I to class IIb.9 More recent analyses have shown that morphine
administration is associated with a significant delay in onset of
effective platelet inhibition by clopidogrel,
10
158
and has
159
ticagrelor,
160
and
CHAPTER 12 Adjunctive Pharmacologic Therapies in Acute Myocardial Infarction 133
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prasugrel
161
in patients undergoing primary PCI for STEMI,
potentially by delaying gastric emptying and/or gastrointestinal
absorption of the drugs.
Evidence from multiple observational studies has suggested
that NSAIDs and COX-2 inhibitors (COXIBs) may be associated
with an increased risk of adverse events among patients with
MI receiving antiplatelet therapy, potentially due to interactions
that compete with the beneficial actions of aspirin. Nonselective
NSAIDs in high doses and COXIBs in all dosages have been
observed to increase mortality in patients with previous MI and
should be avoided.
162
Adverse effects of nonselective NSAIDs
are attributed to loss of gastrointestinal protection and hemostasis
via COX-1 inhibition and loss of antiinflammatory activity via
COX-2 inhibition.13 COXIB-induced reduction of PGI2 and
unchecked COX-1 activity result in continued TXA2 production
and increased risk of thrombosis that may be harmful during
acute MI. COXIB-induced antiinflammatory effects may be
beneficial for progression of atherosclerosis but harmful during
infarct healing. Suppression of inflammation by COX inhibitors
can impair infarct healing after STEMI and lead to infarct thinning, adverse LV remodeling, aneurysm formation, and cardiac
rupture,13 suggesting the need for caution.
The FDA issued a warning on the concomitant use of aspirin
and the NSAID ibuprofen. Ibuprofen (but not rofecoxib, acetaminophen, or diclofenac) interferes with aspirin-induced
acetylation of COX-1 and attenuates its effects. The FDA also
warned that COXIBs increase cardiovascular risk; rofecoxib
(Vioxx) was withdrawn from the market, although celecoxib
and valdecoxib remain. Based on evidence that patients taking
NSAIDs within the week before MI have an increased risk of
death, hypertension, reinfarction, heart failure, myocardial
rupture, or shock, NSAIDs and COXIBs are contraindicated in
patients with STEMI. It is recommended that they should not
be initiated in the acute phase of MI and should be discontinued
in any patients using them prior to hospitalization for acute MI.
A stepped-care approach to use of these agents for patients with
cardiovascular disease has been recommended.
163
Recommendations
Morphine remains recommended for the relief of continuing
pain in STEMI patients.10 Nevertheless, given recent concerns
raised about the possible hazard of morphine administration,
initial efforts to relieve pain by relieving ischemia with nitrates
and β-blockers are reasonable with morphine use restricted to
select patients in whom the need appears to outweigh the risks.
NSAIDs and COXIBs are contraindicated and should be avoided
in patients with STEMI. The ACC/AHA guidelines regarding
use of morphine and other analgesics are summarized in the
Appendix.
CHOLESTEROL-LOWERING THERAPY
In the hospital phase of acute MI treatment, determination of a
patient’s lipid profile and initiation of interventions to manage
dyslipidemia and promote secondary prevention have been part
of routine management, although recent guidelines suggest that
all such patients should be treated without attention to lipid
levels or targets. Hydroxymethylglutaryl–coenzyme A (HMG-CoA)
reductase inhibitors (statins) have been extensively investigated
and are established as an important drug class for both lowering
atherogenic lipids and reducing future adverse cardiovascular
events.
Statins are competitive inhibitors of the rate-limiting step in
cholesterol synthesis. All statins reduce low-density lipoprotein
(LDL) cholesterol; some also increase high-density lipoprotein
(HDL; e.g., simvastatin, rosuvastatin) and reduce triglycerides
(e.g., atorvastatin, rosuvastatin). Aggressive lipid lowering has been
shown to decrease atheroma burden and is beneficial in all patients
with coronary artery disease. The Reversal of Atherosclerosis with
Aggressive Lipid Lowering (REVERSAL) trial showed that aggressive lipid lowering prevented progression of atheroma in patients
with known coronary artery disease.
164
In A Study to Evaluate
the Effect of Rosuvastatin on Intravascular Ultrasound-Derived
Coronary Atheroma Burden (ASTEROID), very-high-intensity
statin therapy induced regression of coronary atherosclerosis.
165
Although the mechanism of benefit is not completely understood,
abundant evidence shows reduction in mortality with lowering
of cholesterol in patients with hypercholesterolemia after MI
even patients with mild cholesterol elevation
169
levels
derive benefit.
167,168
or normal LDL
166
;
The benefit of statin therapy for secondary prevention has
been well established by 25 years of clinical investigation. Several
trials have specifically studied the effect of statins on outcome
in patients following ACS or acute MI. In the Cholesterol and
Recurrent Events (CARE) trial,
168
4159 patients with total
cholesterol levels less than 240 mg/dL were randomized to
pravastatin 40 mg/day or placebo 3 to 20 months after acute
MI. After a median follow-up of 5 years, the rate of fatal coronary
events or nonfatal MI was reduced by 24%, the frequency of
stroke by 31%, the rate of coronary bypass surgery by 26%, and
the rate of coronary angioplasty by 23%.
In the Myocardial Ischemia Reduction with Aggressive
Cholesterol Lowering (MIRACL) trial,
170
3086 patients with
unstable angina or non-Q-wave MI were randomly assigned to
treatment with high-dose atorvastatin (80 mg/day) or placebo
between 24 and 96 hours after admission. At 16-week follow-up,
atorvastatin reduced LDL cholesterol by an average of 52%. The
primary composite endpoint of death, nonfatal MI, cardiac arrest
with resuscitation, or recurrent symptomatic myocardial ischemia
was reduced 16% by atorvastatin.
The question of the benefit of early initiation of statins after
acute MI was addressed in a prospective, nonrandomized cohort
study using the Swedish Register of Cardiac Intensive Care
(RIKS-HIA).
171
The study population consisted of nearly 20,000
patients with a first MI, of whom 5528 received statins at or
before discharge and 14,071 did not. Early statin treatment started
before hospital discharge was associated with a 25% reduction
in 1-year mortality. Similarly, in an observational study
172
of
patients with ACS from the GUSTO IIb and PURSUIT trials,
the mortality rate at 6 months was 33% lower among the 3653
patients discharged on lipid-lowering agents compared with the
17,156 patients who were not.
The question of whether intensive (vs. moderate) lipid lowering
would have greater benefit for high-risk patients with ACS was
134 PART III Coronary Artery Disease
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tested in the Pravastatin or Atorvastatin Evaluation and Infection
Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE
IT-TIMI 22) trial.
169
In that study, 4162 patients were randomly
assigned to 40 mg of pravastatin or 80 mg of atorvastatin within
10 days of hospitalization for an ACS. During the trial, the median
cholesterol levels of the pravastatin and atorvastatin groups were
95 mg/dL and 62 mg/dL, respectively. By 2 years, there was a
significant (16%) reduction in the composite of death from any
cause, MI, unstable angina requiring rehospitalization, revascularization, and stroke among patients assigned to atorvastatin
treatment. The study demonstrated that among patients with
recent ACS, compared with standard treatment to moderate
goals, intensive lipid-lowering treatment provides significantly
greater protection against death and major cardiovascular
events.
These data suggested that, after STEMI, patients should be
started on high-intensity statins and continued after discharge
to reduce short- and long-term adverse cardiovascular events.
Starting therapy while the patient is in the hospital improves
adherence with no noted adverse effects
173
and adherence improves
survival.2 The modified Adult Treatment Panel (ATP) III guidelines
174
in 2004
suggested that, for high-risk patients, the recommended
LDL-C treatment goal is less than 100 mg/dL. However, a target
of less than 70 mg/dL represents a reasonable therapeutic option
for persons considered to be at very high risk, such as patients
after AMI.
Of note, however, the most recent ACC/AHA guideline for
treatment of blood cholesterol
175
did not support titrating
cholesterol-lowering drug therapy to achieve optimal LDL-C or
non-HDL-C levels. Instead, they strongly recommended that all
individuals 75 years of age or younger who have clinical atherosclerotic cardiovascular disease (ASCVD), including all patients
following acute MI, should be treated with high-intensity statin
therapy unless contraindicated. High-intensity therapy was defined
as treatment that lowers LDL-C by more than 50%; moderateintensity statin therapy lowers LDL-C by 30% to 50%, and
low-intensity statin therapy lowers LDL-C by less than 30%.
High-intensity statins include atorvastatin at 80 mg daily and
rosuvastatin at 20 mg daily. The guidelines also stated that for
such patients, when high-intensity statin therapy is contraindicated or when characteristics predisposing to statin-associated
adverse effects are present, moderate-intensity statins should be
used as the second option, if tolerated.
There is recent evidence that lowering LDL cholesterol to
levels below previous targets provides additional benefit. The
Improved Reduction of Outcomes: Vytorin Efficacy International
176
Trial (IMPROVE-IT)
randomly assigned 18,144 patients who
had been hospitalized for an ACS within the preceding 10 days
to simvastatin at 40 mg or a combination of simvastatin (40 mg)
and ezetimibe (10 mg; simvastatin–ezetimibe). Over a follow-up
of 7 years, the average LDL cholesterol for the simvastatin
monotherapy group was 69.5 mg/dL compared with 53.7 mg/
dL in the simvastatin–ezetimibe group. At 7 years, the addition
of ezetimibe to simvastatin resulted in a significant reduction
in the composite endpoint of cardiovascular death, MI, unstable
angina requiring rehospitalization, coronary revascularization,
or stroke with no increase in side effects. The investigators
concluded that, when added to statin therapy, ezetimibe resulted
in incremental lowering of LDL cholesterol levels and improved
cardiovascular outcomes.
The effect of more powerful lipid lowering by a new class
of agents, the proprotein convertase subtilisin–kexin type 9
(PCSK9) inhibitors, has recently been investigated. Evolocumab is
a monoclonal antibody PCSK9 inhibitor that has been shown to
lower LDL cholesterol levels by approximately 60%. The effect of
evolocumab on outcomes for patients with ASCVD was assessed
in the Further Cardiovascular Outcomes Research With PCSK9
Inhibition in Subjects With Elevated Risk (FOURIER) trial,
177
in which 27,564 patients with ASCVD and LDL cholesterol
levels of 70 mg/dL or higher who were receiving statin therapy
were randomly assigned to receive evolocumab or placebo. At
48 weeks, the median LDL cholesterol level in the evolocumab
group was 30 mg/dL and, in 42% of patients, evolocumab
lowered LDL cholesterol to 25 mg/dL or lower. Over 2.2 years
of follow-up, evolocumab treatment significantly reduced the
risk of cardiovascular death, MI, stroke, hospitalization for
unstable angina, or coronary revascularization without an
increase in adverse events other than infrequent minor injection site reactions. Currently, the PCSK9 inhibitors are costly,
with restricted indications for use that state it can be prescribed
as an adjunct to diet and maximally tolerated statin therapy
for the treatment of select adults with heterozygous familial
hypercholesterolemia or ASCVD who require additional lowering
of LDL-C.
Recommendations
STEMI patients represent a high-risk ASCVD group in need of
aggressive secondary prevention; high-intensity statin treatment
(e.g., atorvastatin 80 mg daily or rosuvastatin 20 mg daily) is
recommended for all patients without contraindications or a
history of intolerance. Additional cholesterol-lowering interventions have been shown to be beneficial, as discussed earlier, and
may be considered on an individual basis for select patients for
whom statin therapy is not feasible or does not achieve the desired
lowering of LDL. The ACC/AHA guidelines for lipid management
in STEMI are summarized in the Appendix.
ANTICOAGULANTS
The use of anticoagulants in the acute and convalescent phases
of STEMI has evolved with dramatic changes in management
strategy. Current parenteral anticoagulants potentially useful
during the acute phase of STEMI include unfractionated heparin
(UFH), low-molecular-weight heparin (LMWH), fondaparinux,
and bivalirudin (Table 12.6). The selection of one of these agents
for early management may vary based on reperfusion strategy, as
discussed later, and assessment of the patient’s risk of bleeding.
Oral anticoagulants include the vitamin K–dependent antagonist,
warfarin, and the non-vitamin K–dependent oral anticoagulants
(NOACs). The NOACs include dabigatran, which directly inhibits
thrombin, and apixaban and rivaroxiban, which inhibit factor
Xa. NOACs have not been adequately studied in the setting
of STEMI.
CHAPTER 12 Adjunctive Pharmacologic Therapies in Acute Myocardial Infarction 135
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TABLE 12.6 Duration of Antiplatelet and
Anticoagulant Therapy Following ST
Elevation Myocardial Infarction
Duration of Therapy
Oral Antiplatelet Therapy
Aspirin Lifelong
Clopidogrel/
prasugrel/
ticagrelor
Anticoagulant Therapy
Unfractionated
heparin
(intravenous)
Low-molecular-
weight heparin
Fondaparinux
Bivalirudin Up to 3 days, provided no other contraindications to
Warfarin If patient has left ventricular thrombus or aneurysm, 3
Thrombin is a key protease of the coagulation system.
Thrombin inhibitors (UFH and LMWH) prevent the formation
of thrombin and inhibit the activity of already formed thrombin.
UFH is a mixture of glycosaminoglycan chains that produces
its anticoagulant effect by binding to antithrombin III, which
inactivates factor IIa (thrombin), factor IXa, factor Ia, and factor
Xa (see Fig. 12.1). UFH prevents growth of existing thrombus,
but does not lyse clot.
tion of factor Xa than thrombin, whereas UFH produces equal
inhibition of factor Xa and thrombin. Fondaparinux is a synthetic
heparin polysaccharide that binds to antithrombin with higher
affinity than either UFH or LMWH and causes a conformational
change that results in a preferential increase in the ability of the
antithrombin–fondaparinux complex to inactivate factor Xa.
Direct thrombin inhibitors, such as hirudin and bivalirudin,
bind and inactivate thrombin without need for a cofactor, but
have little effect on generation of thrombin. Bivalirudin is a
synthetic analogue of hirudin that binds reversibly to thrombin
and inhibits clot-bound thrombin.
In GUSTO-1,
heparin and systemic alteplase and streptokinase were studied,
an optimal activated partial thromboplastin time of between 60
and 70 seconds was associated with the lowest mortality, fewest
bleeding complications, lowest reinfarction rate, and lowest
If patient had bare metal stent, minimum 1 month, or
1 year post-ACS
If patient had drug-eluting stent, minimum 1 year,
longer for select cases
If patient has not been revascularized, can continue
clopidogrel or ticagrelor for up to 1 year
Up to 48 h, provided no other contraindications to
discontinuation
Can discontinue when patient has been revascularized
by stenting
Up to 8 d or duration of hospitalization, provided no
other contraindications to discontinuation
Can discontinue when patient has been revascularized
by stenting
Up to 8 d or duration of hospitalization, provided no
other contraindications to discontinuation
Can discontinue when patient has been revascularized
by stenting
discontinuation
Can discontinue when patient has been revascularized
by stenting
months to lifelong therapy
178
LMWH produces more potent inactiva-
152
in which intravenous and subcutaneous
frequency of hemorrhagic shock. Intravenous heparin should
be given cautiously or not at all when streptokinase is used,
unless it is specifically indicated. Prolonged heparin is effective
in preventing LV thrombus after acute MI.
179
One advantage of LMWH over UFH is that it does not require
blood monitoring for titrating the dose to a therapeutic activated
partial thromboplastin time. LMWH is renally cleared; thus it
should be avoided in patients with renal failure. Side effects with
both types of heparin include bleeding, thrombocytopenia, and
osteoporosis. Patients at high risk for bleeding include women,
patients over 65 years of age, and patients with comorbid states
such as peptic ulcer, liver disease, and malignancy. Intravenous
protamine can be used to reverse UFH but only partially
reverses LMWH.
Heparin-induced thrombocytopenia (HIT) is a well-known
complication of UFH and LMWH therapy. Two types of HIT
are recognized.
180
HIT type I occurs in the first 4 days with a
platelet nadir of 100,000/mL, resolves even with continued therapy,
and is not thought to be immune related. HIT type II occurs
within 5 to 10 days in 1% to 3% of patients and is immune
mediated. It should be suspected when the platelet count decreases
more than 50%, if venous or arterial thrombosis develops, or if
there is necrosis noted at heparin injection sites. LMWH is
associated with lower rates of HIT than UFH, but should nevertheless still be avoided in patients with HIT.
181
Monitoring of platelet counts is recommended for patients
on heparin or LMWH. Patients exposed to heparin during the
previous 3 months can develop early HIT type II mediated by
circulating antibodies. Management of HIT type II includes
immediate discontinuation of LMWH or UFH with careful
attention to avoidance of routine heparin flushes and heparinbonded catheters.
182
Patients who have a history of HIT type II
should not be reexposed to either type of heparin because a
recurrence can be expected 2 to 3 days after reexposure. STEMI
patients with HIT or a history of HIT who require anticoagulation
should be treated with a nonheparin anticoagulant, such as
bivalirudin or argatroban.
Anticoagulant therapy in conjunction with thrombolytic
therapy or primary PCI is addressed in detail elsewhere. For
patients receiving fibrinolytic therapy, clinical trials support the
use of unfractionated heparin, enoxaparin, and fondaparinux.
For patients receiving primary PCI, evidence supports the
adjunctive use of UFH and bivalirudin. Fondaparinux is not
recommended in patients undergoing primary PCI owing to an
increased risk of thrombotic procedural complications.
There have been no randomized controlled studies or new
data to guide the management of STEMI patients who do not
undergo reperfusion therapy. In ISIS-2, patients who were treated
with aspirin and subcutaneous UFH did not show a survival
advantage over those treated with intravenous heparin.
12
Although
postlytic intravenous UFH increased bleeding in other trials, a
statistically nonsignificant 18% decrease in mortality was also
183
found.
It is recommended that STEMI patients who require anticoagulation be given UFH as an intravenous infusion, with a bolus
of 60 U/kg (maximum 4000 U) followed by infusion of 12 U/
kg/hour (maximum 1000 U/hour). Weight-based initial dosing
136 PART III Coronary Artery Disease
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for intravenous heparin is preferred because of evidence that
the effects of heparin are primarily mediated by weight.
184
A
useful target is an activated partial thromboplastin time range
of 50 to 70 seconds or 1.5 to 2 times control values based on
data showing that values above this increase bleeding, stroke,
and mortality, whereas lower values are associated with increased
mortality. After thrombolytic therapy, anticoagulation can be
continued for 48 hours or longer in patients at high risk for
thromboembolism, such as those with anterior STEMI, severe
LV dysfunction, CHF, history of systemic or pulmonary embolization, atrial fibrillation, or echocardiographic evidence of LV
thrombus.
185
Anticoagulation is generally not continued after
revascularization of the infarct-related artery by PCI unless there
are specific indications (discussed later).
LMWH for the management of STEMI has also been studied.
The Clinical Trial of Reviparin and Metabolic Modulation in
Acute Myocardial Infarction Treatment Evaluation (CREATE)
186
randomly assigned 15,570 patients in India and China presenting
with STEMI or new left bundle branch block, who had reperfusion
therapy with either primary PCI or thrombolytic therapy, to
LMWH (reviparin) or placebo. LMWH improved 30-day survival
and reduced reinfarction regardless of whether the patient had
primary PCI, lytic therapy, or no reperfusion therapy.
The effect of the factor Xa inhibitor fondaparinux (2.5 mg/
day) was studied in the Organization for the Assessment of
Strategies for Ischemic Syndromes (OASIS-6) trial of 12,092
STEMI patients.
187
The patients were divided into two strata.
The first stratum, consisting of 5658 patients with no indication
for heparin, was assigned to fondaparinux 2.5 mg daily for up
to 8 days, or placebo; the second stratum, consisting of 6434
patients with an indication for heparin (e.g., fibrin-specific
thrombolytic, primary PCI or no reperfusion), was assigned to
fondaparinux for up to 8 days or UFH for 48 hours. Fondaparinux
reduced 30-day mortality or reinfarction from 11.2% to 9.7%
compared to control with benefits apparent at 9 days and driven
primarily by reductions in stratum 1. In stratum 2, patients who
were not managed with primary PCI, fondaparinux was superior
to UFH in preventing death or reinfarction at 30 days. The overall
findings indicated that in STEMI patients who are not managed
with primary PCI, fondaparinux reduces mortality and reinfarction without increasing bleeding and strokes.
187
There are some theoretical advantages in using a direct
thrombin inhibitor over heparin. After thrombolytic therapy, a
procoagulant state is induced by thrombin bound to soluble
fibrin derivatives. In contrast to direct thrombin inhibitors, a
heparin–antithrombin III complex is unable to inactivate
thrombin within a clot because it cannot penetrate the clot.
188
The direct thrombin inhibitor, bivalirudin, has been studied in
patients undergoing thrombolytic therapy
undergoing primary PCI.
190,191
189
and in patients
Oral Anticoagulation
Following acute MI, increased thrombin generation and increased
activity of the coagulation system may persist for several months;
this may account, at least in part, for a heightened risk of
recurrent ischemic events.
oral anticoagulant reduces the risk of recurrent events after MI
192
The question of whether chronic
for patients with no other indications for anticoagulation has
been evaluated in clinical trials that have included warfarin
and NOACs.
Warfarin inhibits the vitamin K-dependent synthesis of
biologically active forms of the clotting factors II, VII, IX, and
X, as well as the regulatory factors protein C, protein S, and
protein Z. Dosing of warfarin is highly variable between patients
and should be titrated by assessing the patient’s response through
the international normalized ratio (INR). The antithrombotic
properties of warfarin do not occur for 72 to 96 hours after
initiation of treatment. Its major side effect is bleeding related
to its anticoagulant effect, which may be reversed with vitamin
K or fresh frozen plasma. Warfarin-induced skin necrosis is a
rare condition in which skin and subcutaneous tissue necrosis
occurs owing to acquired protein C deficiency following treatment
with warfarin.
The use of oral anticoagulation with warfarin for secondary
prevention following MI has been studied in several randomized
clinical trials. These trials were conducted before the common
use of early invasive management with PCI and among select
patients at relatively low risk for bleeding. In general, these trials
showed modest benefit for warfarin with respect to reduction of
composite ischemic endpoints, but none showed a reduction in
mortality and all reported a 20% to 35% rate of drug discontinuation and a higher rate of bleeding with warfarin therapy.
Two meta-analyses comparing warfarin plus aspirin to aspirin
alone suggested that when the INR was maintained at 2.0 to
3.0, warfarin plus aspirin was associated with a reduction in the
risk of ischemic events but there was no significant difference
in the overall risk of major ischemic events and there was a
significant increase in major bleeding.
193,194
Notably, none of
the trials included patients treated with primary PCI or DAPT,
limiting the applicability of warfarin for this indication in current
practice.
Therefore, following STEMI, it is recommended that warfarin
use be restricted to patients with other indications for anticoagulation, such as atrial fibrillation, documented LV thrombus, or a
large akinetic or dyskinetic LV segment. There have been no
randomized controlled studies of warfarin for LV thrombus. A
meta-analysis of observational studies showed that anticoagulated
patients had an 86% reduction in embolization rate.
most embolic events occur early, anticoagulation with warfarin
for 3 months is recommended for STEMI patients with an LV
thrombus.10 When warfarin is combined with aspirin, the dose
of aspirin should be kept low (75 to 81 mg) and the INR should
be maintained in the range of 2.0 to 3.0.
LV aneurysm is a common complication of STEMI if reperfusion has not been attempted or achieved. Approximately 50%
of LV aneurysms have a thrombus.
195
Patients with an LV
aneurysm and thrombus after recent MI are at high risk of
emboli—13% over a 6- to 15-month follow-up period—and
should be anticoagulated. Chronic LV aneurysms have a lower
risk of embolization—0.35% over a 5-year follow-up period—as
the thrombus becomes organized. Warfarin is not warranted in
these patients unless other indications are present.
The effects of two NOACs, apixaban and rivaroxaban, have
also been studied in post-ACS populations with no other
185
Since
CHAPTER 12 Adjunctive Pharmacologic Therapies in Acute Myocardial Infarction 137
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indications for anticoagulation. Apixaban is an oral factor Xa
inhibitor approved for the treatment of deep vein thrombosis
(DVT) and pulmonary embolism, prevention of DVT in postoperative patients, and for the prevention of systemic embolic
events in patients with nonvalvular atrial fibrillation. In the
Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2)
196
trial,
7392 patients with an ACS within the previous 7 days
receiving DAPT were randomly assigned to apixaban 5 mg twice
daily or placebo. The trial was stopped early owing to an increase
in the rate of major bleeding in the apixaban group, while the
rate of ischemic events at that time point (241 days) appeared
similar in the 2 groups.
Rivaroxaban is an oral factor Xa inhibitor that is approved
for reducing the risk of systemic embolic events and stroke in
patients with nonvalvular atrial fibrillation as well as for the
treatment of DVT and pulmonary embolism. It was studied in the
setting of ACS in the Anti-Xa Therapy to Lower Cardiovascular
Events in Addition to Standard Therapy in Subjects with Acute
Coronary Syndrome–Thrombolysis in Myocardial Infarction 46
(ATLAS ACS–TIMI 46) trial,
197
which randomly assigned 15,526
patients within 7 days of hospitalization for ACS to twice-daily
doses of either 2.5 mg (very low dose) or 5 mg (low dose) of
rivaroxaban (one-quarter and one-half, respectively, of the full
anticoagulation dose) or placebo. In this trial, approximately 50%
of patients had STEMI, 25% had NSTEMI, 25% had unstable
angina, 93% were also receiving DAPT, and patients with prior
ischemic stroke or transient ischemic attack were excluded. At
13 months, the composite of death from cardiovascular causes,
MI, or stroke and the rate of stent thrombosis were reduced
by 16% by rivaroxaban (pooled dose groups vs. placebo); a
lower rate of cardiovascular death was observed among patients
receiving the very low 2.5 mg dose. Rivaroxaban also increased
the rate of major bleeding and intracranial hemorrhage, but
not fatal bleeding. Among the 7817 patients with STEMI in
the trial, rivaroxaban significantly reduced the risk of recurrent
ischemic events by 19% but also significantly increased major
bleeding.
198
Of note, rivaroxaban was approved in 2013 by the European
Medicines Agency for the prevention of cardiovascular events
in patients following an ACS. However, in the United States,
an FDA advisory panel reviewed but voted against approval of
an expanded indication for rivaroxaban to reduce the risk of
secondary cardiovascular events in patients with ACS, citing
incomplete safety data from the trial. Rivaroxaban is not recommended in current guidelines for treatment of patients following
STEMI.
In some patients following STEMI or NSTE ACS, chronic
oral anticoagulation may be indicated to lower the risk of
thromboembolism or prosthetic valve dysfunction, such as those
with atrial fibrillation, LV systolic dysfunction or thrombus, or
prosthetic heart valves. Since such patients also have indications
for DAPT, the use of chronic anticoagulation has raised challenging issues regarding managing bleeding risk and determining
optimal regimens.
Among patients following PCI with stent implantation,
observational studies examining the use of warfarin combined
with both aspirin and clopidogrel (“triple therapy”) have suggested
a significantly increased risk of major bleeding. For this reason,
for patients undergoing primary PCI who require anticoagulation,
avoidance of a drug-eluting stent has been recommended to
limit the required duration of triple therapy. When triple therapy
is used, an INR targeted to a range of 2.0 to 2.5 is recommended
with low-dose aspirin (75–81 mg) and no more than 75 mg/day
of clopidogrel. Patients who have had PCI with stenting and are
prescribed triple therapy after an ACS and who are without
recurrent events at 1 year may be considered to have stable disease
and the P2Y12 antagonist can be discontinued. Prasugrel and
ticagrelor are not recommended as part of triple therapy. Based
on a strategy examined in the What Is the Optimal Antiplatelet
& Anticoagulant Therapy in Patients With Oral Anticoagulation
and Coronary Stenting (WOEST) study,
199
some have advocated
that, when warfarin is indicated following MI in patients who
have received a drug-eluting stent, discontinuation of the aspirin
from triple therapy and continuation of warfarin plus clopidogrel
may reduce bleeding complications yet maintain a low risk of
thrombotic events such as stent thrombosis. It should be recognized that a small minority of the patients in the WOEST trial
presented with ACS and the risk of stent thrombosis may therefore
have been lower than in a post-STEMI population.
Novel strategies using combinations of rivaroxaban at low
dose and DAPT or a P2Y12 antagonist alone were recently tested
in the Open-Label, Randomized, Controlled, Multicenter Study
Exploring Two Treatment Strategies of Rivaroxaban and a DoseAdjusted Oral Vitamin K Antagonist Treatment Strategy in
Subjects with Atrial Fibrillation who Undergo Percutaneous
Coronary Intervention (PIONEER AF-PCI) study
200
and were
compared to standard triple therapy. Rivaroxaban-containing
regimens had lower bleeding rates than standard triple therapy
but the trial was small and no firm conclusions on efficacy or
safety to guide practice were possible. Further study is needed
to guide the use of anticoagulants, when indicated, in combination
with antiplatelet therapy among patients following MI and PCI.
Recommendations
Patients with STEMI who undergo primary PCI should be
anticoagulated with UFH or bivalirudin; the choice may be based
on the considerations and preference of the interventional
operator in the context of an assessment of bleeding risk and
interacting medications. Anticoagulation should generally be
discontinued following revascularization, although continuation
of bivalirudin for a limited period after stent implantation may
be considered for select patients to reduce the risk of stent
thrombosis. Patients with STEMI receiving fibrinolytic therapy
should receive anticoagulation using UFH, enoxaparin, or
fondaparinux for at least 48 hours or until revascularization.
At present, following STEMI, warfarin is recommended for
patients with indications for continued oral anticoagulation,
although caution is warranted for patients following primary
PCI with stent implantation receiving warfarin in combination
with DAPT (triple therapy), for whom the bleeding risk may be
very high. Attention to using low-dose aspirin, clopidogrel at
75 mg daily and maintaining the INR in the range of 2.0 to 2.5
is recommended to reduce the bleeding risk in such patients.
138 PART III Coronary Artery Disease
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The ACC/AHA guidelines for anticoagulation in STEMI are
summarized in the Appendix.
CONCLUSION
Adjunctive pharmacologic therapy is important for all STEMI
patients whether they are treated with reperfusion therapy or
not. This therapy can help minimize infarct size; reduce adverse
ventricular remodeling; and reduce reinfarction, recurrent angina,
and mortality. These agents can be used to widen the time frame
for reperfusion therapy and to minimize reperfusion injury and
ventricular dysfunction. Agents of proven benefit include aspirin,
P2Y12 antagonists, β-blockers, ACE inhibitors, ARBs, and
aldosterone antagonists. Attention to early and comprehensive
application of evidence-based therapies starting during the acute
cardiac intensive care phase can significantly improve outcomes
after MI.
Acknowledgment
I acknowledge the contributions of Drs. Jonathan Man, Wayne
Tymchak, and Bodh Jugdutt, who were the authors of this chapter
in the previous edition.
The full reference list for this chapter is available at
ExpertConsult.com.
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