receptor antagonists, ticagrelor, prasugrel, and clopidogrel, have
evolved to become an integral part in the management of ACS. By blocking the P2Y12
adenosine diphosphate receptors, these agents decrease platelet activation and
aggregation, increase bleeding time, and reduce blood viscosity.
antiplatelet potency, pharmacokinetics, pharmacodynamics, pharmacogenomics, and
drug–drug interactions exist between the three agents (Table 13-5). Cangrelor is an
intravenous agent recently approved to reduce the risk of thrombotic events in
patients undergoing PCI. It is for patients who are not being treated with another
inhibitor or a GP IIb/IIIa inhibitor.
28 Compared with the oral agents, cangrelor
has a very rapid onset (2 minutes) and offset of action (1 hour).
versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition
(CHAMPION) PHOENIX trial, the primary composite end point of death, MI,
ischemia-driven revascularization, or stent thrombosis at 48 hours occurred in
significantly fewer patients treated with IV cangrelor compared to oral clopidogrel
(4.7% vs. 5.9%, p = 0.005). Although the benefit persisted at 30 days, it came at the
expense of an increase in bleeding with rates of about one in 170 with cangrelor
versus one in 275 with clopidogrel.
29 Controversy surrounds the use of
pharmacogenomic and platelet function testing when determining whether a patient
may be a “responder” or “nonresponder” to clopidogrel therapy.
ACC/AHA guidelines do not recommend routine testing for genetic variants. See
Chapter 12, Chronic Stable Angina, for greater detail about these controversies.
Vorapaxar is an oral antiplatelet that selectively inhibits the cellular actions of
thrombin through antagonism of platelet protease-activated receptor-1. It is indicated
for secondary prevention of cardiovascular events in patients who have a history of
MI or peripheral vascular disease. In the Thrombin-Receptor Antagonist in
Secondary Prevention of Atherothrombotic Ischemic Events (TRA2P–TIMI50) trial,
patients with a history of MI, ischemic stroke, or peripheral arterial disease who
received vorapaxar 2.5 daily had 13% reduction in the combined end point of death
from cardiovascular causes, MI, or stroke (p < 0.001) and a 12% reduction in the
combined end point of cardiovascular death, MI, stroke, or recurrent ischemia
leading to revascularization (p = 0.001) compared to placebo.
receiving vorapaxar had an increase in moderate and severe bleeding including
intracranial hemorrhage. Among patients with a history of stroke, the rate of
intracranial hemorrhage in the vorapaxar group was 2.4% versus 0.9% with placebo
(p < 0.001). About 67% of patients had a history of MI and of these 98% were
receiving concomitant aspirin and 78% a P2Y12
received prasugrel and no patients received ticagrelor.
secondary prevention of thrombotic cardiovascular events in combination with
aspirin and/or clopidogrel, vorapaxar is contraindicated in those with a history of
stroke, transient ischemic attack, or intracranial hemorrhage.
IIb/IIIa in addition to a ASA and a P2Y
inhibitor are delay to angiography, high-risk features, and early recurrent
J Am Coll Cardiol. 2014;64:e1–e228.)
Pharmacologic Properties of Approved Fibrinolytic Drugs
Alteplase Moderate No 54 100 mg 15 mg IV bolus,
Reteplase Moderate No 60 10 + 10 units 10 U IV bolus,
Tenecteplase High No 63 30–50 mg
IV, intravenous; TIMI, Thrombolysis in Myocardial Infarction.
aFor patients = 65 kg; reduced doses for patients weighing <65 kg.
bFor patients <60 kg, 30 mg; 60–69 kg, 35 mg; 70–79 kg, 40 mg; 80–89 kg, 45 mg; 90 kg, 50 mg.
Risk Factors Associated with Bleeding Complications Secondary to Fibrinolytic
Any prior intracranial hemorrhage
Known structural cerebral vascular lesion (e.g., arteriovenous malformation)
Known malignant intracranial neoplasm (primary or metastatic)
Active bleeding or bleeding diathesis (excluding menses)
Significant closed-head or facial trauma within 3 months
Intracranial or intraspinalsurgery within 2 months
Ischemic stroke within 3 months, EXCEPT acute ischemic stroke within 4.5 hours
Severe uncontrolled hypertension (unresponsive to emergency therapy)
Uncontrolled hypertension on presentation (SBP > 180 mm Hg, DBP > 110 mm Hg)
Chronic, severe, poorly controlled hypertension
Prior ischemic stroke > 3 months, dementia, or known intracranial pathology
Puncture of a noncompressible vessel
Recent internal bleeding within 2–4 weeks
Current use of anticoagulants (the higher the INR, the greater the risk for bleeding)
DBP, diastolic blood pressure; INR, international normalized ratio; SBP, systolic blood pressure.
β-Blockers should be administered to patients with ACS unless a contraindication is
present. In patients with ACS receiving either fibrinolytic therapy or PCI, β-blockers
significantly decreased the rates of cardiovascular mortality, recurrent nonfatal MI,
patients without signs of HF, evidence of low output state, increased risk for
cardiogenic shock or other contraindications. Both β-selective and nonselective
agents have been evaluated; however, β-blockers with intrinsic sympathomimetic
activity should be avoided as they lack efficacy data. For patients with tachycardia or
hypertension without signs of HF, IV β-blockers followed by oral administration can
be considered. Unless there are contraindications to their use, β-blocking agents
should be prescribed for all patients after an AMI, and should be continued
Comparison of P2Y12 Receptor Inhibitors
Parameter Clopidogrel Prasugrel Ticagrelor Cangrelor
Administration Oral Oral Oral Intravenous
Weight – If < 60 kg consider 5
Receptor Binding Irreversible Irreversible Reversible Reversible
Activation Prodrug, limited by
Bioavailability ˜50% 80%–100% 36% NA
Onset of action 2–6 hours 30 minutes 0.5–2 hours 2 minutes
Peak platelet inhibition 300 mg LD (6
Duration 3–10 days 5–10 days 1–3 days 1–2 hours
Half-life 6 hours 7 hours 7 hours 3–6 minutes
CYP2C19 Allele Significant Nonsignificant Nonsignificant Nonsignificant
Increased >Clopidogrel >Clopidogrel
CABG major bleeding Increased >Clopidogrel =Clopidogrel
Safe in stroke Yes Contraindicated Similar stroke rate
Dyspnea/bradyarrhythmia No No Yes Yes
Platelet inhibition ˜50% ˜70% >80% 100%
Drug–Drug Interactions PPIs inhibit CYP
CABG hold time 5 days 7 days 5 days 1 hour
nonsteroidal antiinflammatory drugs; PPIs, proton-pump inhibitors; TIA, transient ischemic attack.
β-Hydroxy-β-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) reduce
long-term morbidity and mortality in patients with cardiovascular disease. Beyond
their lipid-lowering properties, statins are believed to exhibit pleiotropic effects,
which include plaque stabilization, anti-inflammation, antithrombogenicity,
enhancement of arterial compliance, and modulation of endothelial function.
regarding early intensive statin therapy in patients with STEMI or NSTE-ACS exist
with atorvastatin, simvastatin, pravastatin, rosuvastatin, and fluvastatin.
ACC/AHA cholesterol guidelines shift away from specific low-density lipoprotein
(LDL) targets, instead advocating for fixed doses of statins to reduce cardiovascular
risk. Following an AMI, patients should receive a high-intensity statin such as
atorvastatin 40 to 80 mg or rosuvastatin ≥ 20 mg daily. Lower doses could be
considered in patients > 75 years of age or those unable to tolerate higher doses
(see Chapter 8, Dyslipidemias, Atherosclerosis, and Coronary Heart Disease).
Other strategies for minimizing myocardial damage include the use of vasodilators in
the peri-infarction period. Progressive LV dilatation (“remodeling”) occurs in some
patients after an AMI and has become an important marker for prognosis.
Vasodilators reduce oxygen demand and myocardial wall stress by reducing
afterload or preload and can attenuate the remodeling process. Some vasodilators
may increase the blood supply to the myocardium by enhancing coronary
ACE inhibitors have been assessed in a large number of clinical trials, and all
trials using oral agents have demonstrated a reduction
Intravenous ACE inhibitors should be avoided because they cause
excessive hypotension and do not improve survival. The benefit of ACE inhibitors is
greatest in patients with anterior infarction, signs of HF, or a history of previous
infarction. Ideally, oral ACE inhibitors should be started within 24 hours of
diagnosis, after BP and renal function have stabilized. Initial doses should be low
and then titrated as quickly as possible.
1,5 The ACC/AHA guidelines recommend an
ARB in patients with ACS who cannot tolerate ACE inhibitors. The combination of
an ACE inhibitor and ARB should be avoided because of an increase in adverse
Aldosterone antagonists such as spironolactone and eplerenone have been
associated with improved LV structural remodeling and performance by increasing
LVEF and decreasing LV end-diastolic and end-systolic volumes. In the Eplerenone
Post Acute Myocardial Infarction Heart Failure Efficacy and Survival Study
(EPHESUS), patients with AMI and LV dysfunction (LVEF < 40%) with or without
HF were randomized 3 to 14 days after AMI to receive eplerenone (a selective
aldosterone blocker). Eplerenone was found to decrease long-term mortality as an
adjunct to ACE inhibitors and β-blockers.
35 Aldosterone blockade is recommended
in post-MI patients with a LVEF < 40%, diabetes or symptoms of HF, assuming they
Nitrates dilate venous capacitance vessels and peripheral arterioles. Their
predominant effect is a decrease in preload, with a lesser effect on afterload.
Consequently, nitrates lead to a decrease in both myocardial wall stress and oxygen
demand. Intravenous NTG should be used in patients who have refractory ischemic
discomfort (chest pain), acute HF, and/or hypertension. Hemodynamic targets are a
systolic BP between 100 and 130 mm Hg with a heart rate less than 100
Other vasodilators that have been investigated in the treatment of ACS are the
calcium-channel blockers. There are several proposed mechanisms whereby a
calcium-channel blocker might be beneficial. As a group, they dilate coronary and
peripheral vessels. They also alleviate some of the coronary vasospasm present at
the time of coronary thrombosis. In addition, they are effective anti-ischemic agents
through their action in improving coronary blood supply and reducing myocardial
The ACC/AHA guidelines recommend calcium-channel blockers for patients with
Prinzmetal or variant angina. For such patients, calcium-channel blockers that slow
the heart rate (e.g., diltiazem or verapamil) are recommended. These
nondihydropyridines should not be administered to patients with severe LV
dysfunction or pulmonary edema. The Danish Verapamil Infarction Trial (DAVIT)
evaluated the efficacy of verapamil for patients with ACS.
toward lower MI and mortality rates when verapamil was given to patients with
suspected ACS. Similar reductions in MI and refractory angina rates have been
37 The dihydropyridine calcium antagonists amlodipine
and felodipine have not been evaluated specifically for administration to patients
with ACS, but trials involving normotensive patients with coronary artery disease
(CAD) or hypertensive patients with cardiovascular risk factors have demonstrated
that these agents provide significant benefits in reducing cardiovascular events.
It is important to abolish the patient’s pain as quickly as possible because pain and
anxiety associated with an AMI will contribute to increased myocardial oxygen
demand. If the pain is not relieved by medications (e.g., nitrates, β-blockers), then
additional analgesia may be necessary. Morphine sulfate (2 to 4 mg IV with
increments of 2 to 8 mg IV repeated at 5 to 15 minute intervals) is the analgesic of
choice for management of pain associated with STEMI. In addition to diminishing
pain and anxiety, morphine also has beneficial hemodynamic effects. By reducing
pain and anxiety, the release of circulating catecholamines is diminished, possibly
reducing the associated arrhythmias. Morphine also causes peripheral venous and
arterial vasodilatation, which reduces preload and afterload and, consequently,
myocardial oxygen demand. However, retrospective studies have suggested the
potential for increased mortality in patients with NSTE-ACS receiving morphine;
thus, morphine carries a Class IIb recommendation in the 2014 ACC/AHA NSTEACS guidelines.
40 Clinicians should be aware of potential unwanted side effects of
morphine such as hypotension, nausea, and respiratory depression.
The nonselective and cyclooxygenase (COX)-2–selective nonsteroidal
antiinflammatory drugs (NSAIDs) have been associated with an increased risk of
mortality, reinfarction, hypertension, HF, and myocardial rupture. These agents
should be discontinued at the time a patient presents with ACS.
It is common to administer agents such as docusate to prevent constipation in AMI
patients because straining causes undesirable stress on the cardiovascular system.
Many patients are modestly hypoxemic during the initial hours of an AMI.
Supplemental oxygen should be administered to patients with ACS with an arterial
saturation less than 90%, respiratory distress, or other high-risk features for
hypoxemia. Patients with severe hypoxemia or pulmonary edema may require
intubation and mechanical ventilation.
Ventricular arrhythmias, including ventricular fibrillation, are common complications
associated with myocardial ischemia and AMI as well as a major cause of death.
More than half of the episodes of ventricular fibrillation that occur with an AMI are
within 1 hour of the onset of symptoms. If an antiarrhythmic agent is necessary,
amiodarone is preferred over lidocaine (see Chapter 15, Cardiac Arrhythmias). The
routine use of prophylactic lidocaine or other antiarrhythmic agents to prevent
ventricular tachycardia and ventricular fibrillation is not recommended. Although
lidocaine may reduce the number of episodes of ventricular fibrillation, it may
contribute to an increased number of episodes of asystole.
Suppression of ventricular ectopy after an AMI with the chronic use of oral
antiarrhythmic agents is not recommended. Results of the Cardiac Arrhythmia
Suppression Trial (CAST) showed an increase in mortality in asymptomatic patients
with ventricular ectopy after an AMI who were treated with flecainide, encainide, or
moricizine (see Chapter 15, Cardiac Arrhythmias).
For STEMI, primary PCI is the preferred method for reperfusion as long as it can be
performed in a timely fashion. Specific guidelines have been published by the
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