11. Ischemic Heart Disease - Kelly C. Rogers, PharmD Carrie S. Oliphant, PharmD, BCPS Shannon Finks, PharmD, BCPS (AQ Cardiology)

11-1. Introduction


• Ischemia: Lack of oxygen from inadequate perfusion caused by an imbalance between oxygen supply and demand.

• Ischemic heart disease (IHD): Disease caused most frequently by atherosclerosis. IHD may present as silent ischemia, chest pain (at rest or on exertion), or myocardial infarction (MI).

• Angina: Syndrome classically described as discomfort or pain in the chest, arm, shoulder, back, or jaw. Angina is frequently worsened by physical exertion or emotional stress and usually relieved by sublingual (SL) nitroglycerin (NTG). Patients with angina usually have coronary artery disease (CAD) in at least one large epicardial artery.

• Atypical angina: Transient pain or discomfort lacking one or more of the criteria of classic angina. Atypical angina is more common in women, elderly patients, and diabetics.

• Acute coronary syndrome (ACS): Syndrome encompassing the following:

• Unstable angina (UA)

• Non-ST-segment myocardial infarction (NSTEMI)

• ST-segment myocardial infarction (STEMI)

• Coronary artery disease: Chronic disorder that typically cycles in and out of the clinically defined phases of ACS and asymptomatic, stable, or progressive angina.

• Percutaneous coronary intervention (PCI): Procedure to reopen a partially or completely occluded coronary vessel to restore blood flow.

• Coronary artery bypass graft (CABG): Surgical procedure in which a vein is harvested from the leg and attached to the heart as a new coronary vessel in order to bypass a diseased vessel.

Epidemiology of IHD

IHD is the leading cause of death in the United States for both men and women. It causes as many deaths as cancer, chronic lower respiratory diseases, accidents, and diabetes combined.

Approximately 80 million adult Americans have some type of cardiovascular disease, which includes high blood pressure, coronary heart disease (CHD), heart failure, stroke, and congenital defects. In 2006, 829,072 Americans died of cardiovascular disease—nearly 2,400 per day, which averages to one death every 37 seconds. Approximately every 25 seconds an American will suffer a coronary event, and every minute someone will die from one. In 2006, there were 4,378,000 visits to emergency departments and 72,151,000 physician office visits with a primary diagnosis of cardiovascular disease.

In 2009, the estimated direct and indirect cost of cardiovascular disease is $475.3 billion. CHD, which includes acute MI, angina, atherosclerotic cardiovascular disease, and all forms of chronic IHD, is the single largest killer of American men and women. CHD caused one of every five deaths in the United States in 2005.

In 2009, an estimated 785,000 people will have a new coronary attack. About 470,000 will have a recurrent attack, and approximately 195,000 silent attacks occur per year.

For adults under 40 years of age, the lifetime risk for developing CHD is 49% for men and 32% for women.

11-2. Normal Physiology versus Pathophysiology

Normal Physiology

The arterioles change their resistance and dilate as needed to enable the heart to receive a fixed amount of O2. In response to physical exertion, an increase in blood pressure (BP), or an increase in myocardial oxygen demand (MVO2), the arterioles dilate to maintain O2 supply to the heart.

Note: In atherosclerosis, plaque narrows the conductance vessel, causing the arterioles to dilate under normal or resting conditions to prevent ischemia. With stress or exercise, the vasodilator response is minimal, which causes ischemia and angina.

Pathophysiology Determinants of MVO2

• Heart rate (HR): Tachycardia will increase MVO2.

• Contractility: Increases in contractility will increase MVO2.

• Myocardial wall tension: It depends on ventricular volume and pressure. Increased pressure or enlargement of the ventricle will increase systolic wall force and increase MVO2.

Determinants of Myocardial Oxygen Supply and Flow

Myocardial O2 supply is determined by

• Arterial O2 saturation and myocardial O2 extraction, which are relatively fixed under normal circumstances

• Coronary flow, which is dependent on the luminal cross-sectional area of the coronary artery and coronary arteriolar tone

Limits of flow are as follows: thrombi, spasm, congenital abnormalities, severe anemia, and severe ventricular hypertrophy attributable to hypertension or aortic stenosis (abnormally high oxygen demands).

Autoregulation of coronary blood flow occurs as follows:

• Adenosine, a potent vasodilator, is released from myocardial cells in response to decreased O2 supply (e.g., occlusion); increased sympathetic activity (exercise, mental stress, exposure to cold); increased BP; and increased HR, which leads to increased MVO2.

• Normal arteries respond to the increased demand with increased blood flow and some vasodilation of the large epicardial vessels.

• Atherosclerotic vessels lose this vasodilator response and develop constriction.

Vascular endothelium and control of arteriolar tone

The endothelium is the protective surface of the artery wall that separates the blood from the vascular smooth muscle of the artery wall and promotes smooth muscle relaxation and inhibits thrombogenesis. It secretes substances such as nitric oxide (NO), which produces vasodilation similar to the therapeutic effects of NTG. Additionally, these substances are antithrombotic and anti-inflammatory and can be thought of as defense mechanisms against noxious stimuli.

It also secretes substances that cause vasoconstriction. Normally, there is a beneficial balance between vasodilation and vasoconstriction.

Things that can damage the endothelium (cigarettes, oxidized low-density lipoprotein, hypertension, and PCI) lead to decreased NO production and loss of the endothelium's protective effects, which leads to an imbalance promoting vasoconstriction as the predominant response to stress.


Normally, the distribution of blood flow between the epicardial and endocardial layers is equal during the period when coronary artery filling occurs.

In atherosclerosis, subendocardial blood flow is reduced.

Coronary vasospasm

A coronary vasospasm reduces blood flow, thereby causing ischemia, usually in areas of atherosclerotic plaques.


Atherosclerosis is the most common cause of myocardial ischemia. A decrease in the lumen of coronary arteries attributable to stenosis leads to reduced myocardial perfusion and subsequent ischemia.

Segmental atherosclerotic narrowing is most commonly caused by a plaque, which can fissure, hemorrhage, and cause thrombosis, which then worsens the obstruction, reduces blood flow further, and leads to ACS.

11-3. Diagnostic Procedures


Diagnostic procedures include the following:

• History and physical examination

• Laboratory workup:

• Complete blood count (CBC) with platelet count

• Serial creatine kinase-myocardial bound and troponin levels (enzyme markers specific for myocardial necrosis)

• Activated partial thromboplastin time (aPTT)

• Prothrombin time (PT) and international normalized ratio (INR)

• Fasting lipid panel within 24 hours of admission

• Resting electrocardiogram (ECG)

Exercise Tolerance Test

The following drugs can interfere with the exercise tolerance test (ETT, or treadmill test):

• Digoxin causes abnormal exercise-induced ST depression in about 30% of healthy patients.

• β-blockers and vasodilators alter hemodynamic response to BP:

• Hold four or five half-lives before ETT.

• Withdraw β-blockers gradually to avoid precipitating an attack.

• In some situations, patient may continue anti-ischemic therapy.

• Nitrates can attenuate angina.

• Flecainide may cause exercise-induced ventricular tachycardia.

Stress Imaging

Thallium Stress Test

The thallium stress test is a type of nuclear scanning test.

Pharmacologic stress imaging

In pharmacologic stress imaging, drugs "do the exercise" by increasing MVO2.


• High doses up to 40 mcg/kg per minute cause positive inotropic and chronotropic effects that increase cardiac demand that lead to ischemia.

• This drug is commonly used with an echocardiogram. Side effects include nausea, anxiety, tremor, arrhythmias, angina, and headache.

Dipyridamole, adenosine, and regadenoson

• These drugs induce coronary vasodilation; they are used in conjunction with myocardial perfusion scintigraphy.

• Dipyridamole side effects occur in up to 50% of patients and include angina, headache, nausea, dizziness, flushing, and severe bronchospasm in patients with chronic obstructive pulmonary disease (COPD) or asthma.

• Adenosine side effects occur in up to 80% of patients and include chest pain, headache, flushing, shortness of breath, first-degree atrioventricular (AV) block, and severe bronchospasm in patients with COPD or asthma.

• Regadenoson, a newer agent, has fewer side effects than adenosine. The most common are shortness of breath and headache.

Drug interactions

• Xanthines (theophylline, caffeine) are adenosine receptor antagonists that attenuate the effects of adenosine and dipyridamole.

• β-blockers interact with dobutamine, but the interaction can be overcome by increasing the dose of dobutamine.

Cardiac Catheterization

Cardiac catheterization (also called cath or angiography) involves the following procedure:

• A catheter is inserted into the femoral artery and guided to the heart.

• Radiocontrast dye is injected directly into the coronary arteries.

• The dye shows which arteries are involved and the extent of occlusion.

Complications may arise as follows:

• The patient can have an allergic reaction to iodine in the dye.

• The dye can be nephrotoxic.

• Arterial bleeding from access site, stroke, MI, or in rare cases death may occur.

11-4. Chronic Stable Angina, Prinzmetal's or Variant Angina, and Silent Ischemia

Clinical Presentation

Chronic stable angina

Symptoms are caused by decreased O2 supply secondary to reduced flow.

Angina is considered stable if symptoms have been occurring for several weeks without worsening. Characteristics of stable angina are as follows:

• Pain located over sternum that may radiate to left shoulder or arm, jaw, back, right arm, or neck

• Pressure or heavy weight on chest, burning, tightness, deep, squeezing, aching, viselike, suffocating, crushing

• Duration of 0.5-30.0 minutes

• Symptoms may be precipitated by exercise, cold weather, postprandial, emotional stress, sexual activity

• Pain relieved by SL NTG or rest

Prinzmetal's or variant angina

• This uncommon form of angina is usually caused by spasm without increased MVO2.

• Most patients have severe atherosclerosis.

• Recurrent, prolonged attacks of severe ischemia are characteristic.

• Patients are often between 30 and 40 years old.

• Pain usually occurs at rest or awakens the patient from sleep.

• ECG shows ST-segment elevation, which returns to baseline when the patient is given NTG.

Silent ischemia

• Ischemia in the absence of symptoms is "silent."

• About 75% of ischemic episodes in patients with stable angina are undetected.

• ECG shows ST-segment changes with elevation or depression during activity, but patient experiences no symptoms.

• Silent ischemia occurs in about 20-30% of post-MI patients.

• Of patients with stable angina, 50% have silent ischemia; it is common in diabetics.

Pharmacologic Management

Chronic stable angina

Goals of therapy are as follows:

• To prevent MI and death

• To reduce symptoms of angina and occurrence of ischemia to improve quality of life


• Aspirin decreases the incidence of MI, adverse cardiovascular events, and sudden death.

• Clopidogrel (Plavix) has a greater antithrombotic effect than ticlopidine (Ticlid) and has fewer side effects. Note: Ticlopidine has not been shown to reduce cardiovascular events in stable angina.

• Indications for therapy are as follows:

• Aspirin (75-162 mg daily) is recommended in all patients with chronic IHD (with or without symptoms) in the absence of contraindications.

• Clopidogrel (75 mg daily) is chosen when aspirin is absolutely contraindicated.

• Ticlopidine is not recommended because of its poor side effect profile.

• The combination of clopidogrel plus aspirin is not indicated in patients with stable disease not undergoing PCI.

Anti-ischemic therapy


• Effects on MVO2 are as follows:

• Inhibit catecholamine effects, thereby decreasing MVO2

• Decrease HR (negative chronotrope effects cause a decrease in conduction through the AV node)

• Decrease contractility (negative inotrope effects cause a decrease in force of contraction)

• Reduce BP

• Effects on oxygen supply are as follows:

• β-blockers cause no direct improvement of oxygen supply.

• They increase diastolic perfusion time (coronary arteries fill during diastole) secondary to decreased HR, which may enhance left ventricle (LV) perfusion.

• Ventricular relaxation causes increased subendocardial blood flow.

• Unopposed alpha stimulation may lead to coronary vasoconstriction.

• Dosing is as follows:

• Start low, go slow.

• Titrate to resting HR of 55-60 bpm, maximal exercise HR ≤ 100.

• Avoid abrupt withdrawal, which can precipitate more severe ischemic episodes and MI; taper over 2 days.

• Selection of β-blockers is based on the following factors:

• β-blockers with cardioselectivity have fewer adverse effects; they lose cardioselectivity at higher doses.

• The intrinsic sympathomimetic activity (ISA) with acebutolol, carteolol, penbutolol, and pindolol may not be as effective because the reduction in HR would be minimal; therefore, there is a small reduction in MVO2. β-blockers with ISA are generally reserved for patients with low resting HR who experience angina with exercise.

• Lipophilicity is associated with more central nervous system (CNS) side effects.

• β-blockers should be avoided in patients with primary vasospastic angina.

• β-blockers are preferred in patients with a history of MI, chronic heart failure, high resting HR, and fixed angina threshold.

• Indications for therapy are as follows:

• β-blockers are used as first-line therapy if not contraindicated in patients with prior MI, ACS, or history of heart failure.

• They are often used as initial therapy if not contraindicated in patients without prior MI.

• They are more effective than nitrates and calcium channel blockers (CCBs) in silent ischemia.

• They are effective as monotherapy or with nitrates, CCBs, ranolazine, or a combination thereof.

• They should be avoided in Prinzmetal's angina.

• They improve symptoms 80% of the time.

• All β-blockers are effective, but not all are FDA indicated.

Nitrates (endothelium-independent vasodilators)

• Effects on MVO2 are as follows:

• Peripheral vasodilation leads to decreased blood return to the heart (preload), which leads to decreased LV volume, decreased wall stress, and decreased O2 demand.

• Arterial vasodilation leads to decreased peripheral resistance (afterload), decreased systolic BP, and decreased O2 demand.

• Nitrates can cause a reflex increase in sympathetic activity, which may increase HR or contractility and lead to an increase in O2 demand in some patients. This problem can be overcome with the use of a β-blocker.

• Effects on O2 supply: Dilation of large epicardial coronary arteries and collateral vessels in areas with or without stenosis leads to increased O2 supply.

• Indications for therapy are as follows:

• SL nitroglycerin or NTG spray can be used for the immediate relief of angina.

• Long-acting nitrates should be used as initial therapy to reduce symptoms only if β-blockers or CCBs are contraindicated.

• Long-acting nitrates in combination with β-blockers can be used when initial treatment with β-blockers is ineffective.

• Long-acting nitrates can be used as a substitute for β-blockers if β-blockers cause unacceptable side effects.

• Nitrates are used in patients with CAD or other vascular disease.

• Nitrates are preferred agents in the treatment of Prinzmetal's or vasospastic angina.

• Nitrates improve exercise tolerance.

• They produce greater effects in combination with β-blockers or CCBs.

Calcium channel blockers

• Effects on MVO2 are as follows:

• CCBs act primarily by decreasing systemic vascular resistance and arterial BP by vasodilation of systemic arteries.

• They cause decreased contractility and O2 requirement (all CCBs exert varying degrees of negative inotropic effects): verapamil > diltiazem > nifedipine.

• Verapamil and diltiazem promote additional decreases in MVO2 by decreasing conduction through the AV node, thereby decreasing HR.

• Effects on O2 supply are as follows:

• Increased diastolic perfusion time secondary to decreased HR, which may enhance LV perfusion

• Decreased coronary vascular resistance and increased coronary blood flow by vasodilation of coronary arteries

• Coronary vasodilation at sites of stenosis

• Prevention or relief of vasospastic angina by dilation of the epicardial coronary arteries

• Indications for therapy are as follows:

• CCBs can be used as initial therapy for reduction of symptoms. They are usually second line when β-blockers are contraindicated.

• They are used in combination with β-blockers when initial treatment with β-blockers is not successful.

• They are used as a substitute for β-blockers if initial treatment with β-blockers causes unacceptable side effects.

• Slow-release, long-acting dihydropyridines and nondihydropyridines are effective in stable angina.

• Avoid using short-acting dihydropyridines.

• Newer-generation dihydropyridines, such as amlodipine or felodipine, can be used safely in patients with depressed LV systolic function and can be used in combination with β-blockers.

Combination therapy: β-blockers and nitrates

• β-blockers can potentially increase LV volume and LV end-diastolic pressure. Nitrates attenuate this effect.

• Nitrates increase sympathetic tone and may cause a reflex tachycardia. β-blockers attenuate this response.

Combination therapy: β-blockers and CCBs

• β-blockers and long-acting dihydropyridine CCBs are usually efficacious and well tolerated.

• CCBs, especially the dihydropyridines, increase sympathetic tone and may cause reflex tachycardia. β-blockers attenuate this effect.

• β-blockers and nondihydropyridine CCBs should be used together cautiously because the combination can lead to excessive bradycardia or AV block. The combination can also precipitate symptoms of heart failure in susceptible patients.


• Unlike β-blockers and CCBs, ranolazine's antianginal and anti-ischemic effects occur without causing any hemodynamic changes in BP or HR.

• The mechanism of action is not clearly understood, but it appears to inhibit the late Na current (INa), preventing Ca overload and ultimately blunting the effects of ischemia by improving myocardial function and perfusion.

• Ranolazine is indicated as first-line or add-on therapy in combination with β-blockers, CCBs, or nitrates for management of chronic stable angina.

Angiotensin-converting enzyme inhibitors

• Angiotensin-converting enzyme inhibitors (ACEIs) reduce the incidence of MI, cardiovascular death, and stroke in patients at high risk for vascular disease (data from the Heart Outcomes Prevention Evaluation [HOPE] trial).

• Controversy exists whether all ACEIs are equally effective or whether "tissue ACEIs" provide better protection.

• Low-risk patients with stable CAD and normal or slightly reduced LV function may not benefit from ACEI therapy as greatly as high-risk patients.

• Indications for therapy are as follows:

• ACEIs are used in all patients with left ventricular ejection fraction (LVEF) ≤ 40% and in those with hypertension, diabetes, or chronic kidney disease unless contraindicated.

• They are used in all patients with CAD (by angiography or previous MI) or other vascular disease.

• It is reasonable to consider angiotensin receptor blockers (ARBs) for patients who have hypertension and other indications but who are intolerant of ACEIs, have heart failure, or have had a MI with LVEF ≤ 40%.

Lipid-lowering therapy

• Clinical trials have proved that lipid-lowering therapy should be recommended in patients with established CAD, including chronic stable angina, even if only mild or moderate elevations of LDL (low-density lipoprotein) cholesterol are present.

• Omega-3 fatty acids can be encouraged in either dietary consumption or capsule form (1 g daily) for risk reduction; higher doses are recommended for treatment of elevated triglycerides.

• Therapeutic options to treat triglycerides or non-HDL cholesterol include niacin and fibrates (after LDL-lowering therapy).

• Indications for therapy are as follows:

• Lipid-lowering therapy is used in patients with documented or suspected CAD or CHD risk equivalents and LDL ≥100 mg/dL: target LDL < 100 mg/dL.

• It is used in high-risk patients: target LDL < 70 mg/dL may be appropriate.

• A combination of statins with other lipid-lowering therapy requires careful monitoring for prevention of myopathy, rhabdomyolysis, and elevation of liver enzymes.

Prinzmetal's or variant angina

• β-blockers have no role in management and may increase painful episodes.

• β-blockers may induce coronary vasoconstriction and prolong ischemia.

• Nitrates are often used for acute attacks.

• CCBs may be more effective, may be dosed less frequently, and have fewer side effects than nitrates.

• Nifedipine, diltiazem, or verapamil are all equally effective as single agents.

• Nitrates can be added if there is no response to CCBs.

• Combination therapy with nifedipine + diltiazem or nifedipine + verapamil has been reported to be useful.

• Dose titration is recommended to obtain efficacy without unacceptable side effects.

• Treat acute attacks and provide prophylactic treatment for 6-12 months.

Silent ischemia

• The goal is to decrease the number of episodes, both symptomatic and asymptomatic.

• The initial step is to modify risk factors for IHD (smoking, hypercholesterolemia, hypertension).

• β-blockers have shown improvement in patients with ischemic episodes and are preferred in patients post-MI.

• CCBs are somewhat less effective than β-blockers.

11-5. Unstable Angina or Non-ST-Segment Elevation Myocardial Infarction Pathophysiology


The process of ischemic syndromes involves two essential events:

• Disruption of an atherosclerotic plaque

• Formation of a platelet-rich thrombus

The clinical manifestation depends on the extent and duration of the thrombotic occlusion. In UA or NSTEMI, the thrombus does not completely occlude the vessel.

Pathogenesis and clinical presentations of UA and NSTEMI are similar but differ in severity. Many structural and functional differences in disease pathophysiology exist between men and women. Women present more commonly than men with NSTEMI and are found to have less obstructive coronary disease than men.


• Central or substernal or crushing chest pain can radiate to the neck, jaws, back, shoulders, and arms.

• Patients may present with diaphoresis, nausea, vomiting, arm tingling, weakness, shortness of breath, or syncope.

• Pain may be similar to typical angina except that the occurrences are more severe, may occur at rest, and may be caused by less exertion than typical angina.

• UA and NSTEMI may be incorrectly interpreted as dyspepsia or indigestion.

• Pain is not relieved by SL NTG or rest.

• UA and NSTEMI may evolve into STEMI without treatment.


• Chest pain persisting longer than 5 minutes that is unrelieved by SL NTG or rest

• Cardiac enzymes and ECG changes (

Table 11-1)

[Table 11-1. Cardiac Enzymes and ECG Changes: UA versus NSTEMI/STEMI]

Goals of Therapy

• Completely restore blood flow to the myocardium

• Prevent MI, arrhythmias, and ischemia

Pharmacologic Management of UA and NSTEMI

Morphine, oxygen, nitrates, and aspirin

Indications for therapy are shown in

Table 11-2.

Anti-ischemic therapy

β-adrenergic blockade

• Preference is for an agent without ISA.

• Agents with β1 selectivity are preferred in patients with bronchoconstrictive disease.

• There is no evidence that one agent is superior to another.

• Initial choices include metoprolol, atenolol, and propranolol.

• Indications for therapy are as follows:

• β-blockers can be used in all patients without contraindications.

• The first dose should be given orally within the first 24 hours unless contraindications exist, including signs of heart failure, symptoms of low output state, increased risk of cardiogenic shock, or other relative contraindications (e.g., bradycardia, hypotension, heart block, reactive airway disease).


Nitrates are discussed in Table 11-2.

Calcium channel blockers

• There is no mortality benefit from the use of CCBs; therefore, they are not recommended as first-line therapy.

• Indications for therapy are as follows:

• In patients with contraindications to β-blockers, a nondihydropyridine CCB

[Table 11-2. Morphine, Oxygen, Nitrates, and Aspirin Therapy]

   (verapamil, diltiazem) should be used in the absence of significant LV dysfunction or other contraindications.

• Oral long-acting dihydropyridine CCBs provide additional control of anginal symptoms in patients who are already receiving β-blockers and nitrates.

• Avoid short-acting dihydropyridines.

Inhibition of the renin-angiotensin-aldosterone system

• ACEIs, ARBs, and aldosterone inhibitors are used for inhibition of the renin-angiotensin-aldosterone (RAA) system.

• Indications for therapy are as follows:

• ACEIs should be started orally within the first 24 hours in all patients with UA, NSTEMI, or STEMI with pulmonary congestion or LVEF ≤ 40% unless contraindicated.

• It is reasonable to use ACEIs orally within the first 24 hours of STEMI in patients without pulmonary congestion or LVEF ≤ 40% unless contraindicated.

• ACEIs are recommended for life in those patients post UA or post NSTEMI with heart failure, hypertension, or diabetes unless contraindicated.

• On the basis of the results from the HOPE trial, ACEIs may be considered in all patients post UA or NSTEMI who do not have contraindications.

• ACEIs are recommended indefinitely in all patients post STEMI with LVEF ≤ 40% and for those with hypertension, diabetes, or chronic kidney disease, unless contraindicated.

• ARBs should be given to those patients who are intolerant of an ACEI and who have heart failure, LVEF ≤ 40%, or hypertension. Valsartan and candesartan are the only ARBs that have established efficacy for this indication.

• Unless contraindicated, long-term aldosterone blockade should be prescribed for post-UA, NSTEMI, or STEMI patients already receiving therapeutic doses of ACEIs and BBs who have an LVEF ≤ 40% and either symptomatic heart failure or diabetes.

Antiplatelet therapy


Aspirin is discussed in Table 11-2.


• Thienopyridines include clopidogrel (Plavix) and ticlopidine (Ticlid).

• Inhibition of platelet aggregation is irreversible and takes 2-5 days to achieve full effect. Often clopidogrel or ticlopidine is given in a loading dose for a more rapid effect (within 2 hours).

• Clopidogrel is the preferred agent in this class. Ticlopidine is rarely used because of severe toxicities.

• The mechanism of platelet aggregation for clopidogrel and aspirin (ASA) differs; therefore, their effects are additive.

• Indications for therapy are as follows:

• Clopidogrel is an alternative for patients who are allergic to ASA or who have a gastrointestinal intolerance to ASA.

• Clopidogrel should be combined with ASA in patients undergoing stent implantation for a minimum of 1-12 months, depending on the type of stent used and bleeding risk.

• In patients who do not undergo a PCI procedure, clopidogrel 75 mg daily should be combined with ASA for at least 1 month and ideally up to 12 months.

Glycoprotein IIb/IIIa receptor inhibitors (GPIs)


• Abciximab (ReoPro)

• Eptifibatide (Integrilin)

• Tirofiban (Aggrastat)


• All of the agents can be used as adjunctive therapy in patients undergoing PCI.

• In combination with heparin and ASA, eptifibatide and abciximab have been shown to reduce the incidence of combined death, MI, and recurrent ischemia in patients with UA or NSTEMI who undergo PCI.

• GPIs are alternatives to clopidogrel when the appropriate loading dose was not given prior to PCI.

• Abciximab is used only when PCI will likely be done shortly after starting infusion.

• Eptifibatide and tirofiban are the preferred agents if PCI will be delayed.

• Special attention should be focused on proper dosage adjustments of renally cleared agents, especially in elderly patients, women, and those with renal insufficiency.

• Indications for therapy are as follows:

• GPIs can be considered as an adjunct to ASA, clopidogrel, and anticoagulation during PCI.

• GPIs can be given during the intervention procedure just before stent deployment or angioplasty.

• GPIs can be given upstream (prior to PCI) with aspirin +/- clopidogrel, depending on risk factors.

• Upstream eptifibatide and tirofiban are preferred over abciximab.

• These agents are appropriate to use in patients who are not given a clopidogrel loading dose upstream or in cases where the loading dose was not given more than 2-6 hours prior to PCI.

Anticoagulant therapy

Unfractionated heparin

• Heparin or enoxaparin should be given to all patients in combination with ASA and clopidogrel.

• Heparin is continued for a total of 24-48 hours or until a PCI procedure is completed.

• In patients with a planned CABG within 24 hours, heparin use is preferred to low molecular weight heparin (LMWH).

Low molecular weight heparin and anti-Xa inhibitors

• Enoxaparin (Lovenox) is an LMWH.

• LMWH differs from unfractionated heparin (UFH) in size and affinity for thrombin.

• Advantages of LMWH over UFH include better bioavailability, a more predictable response, ease of administration, fewer side effects, and no recommended routine monitoring.

• Trials comparing UFH to LMWH for the treatment of UA and NSTEMI have shown superiority of enoxaparin over UFH, whereas trials with dalteparin showed equivalence to UFH.

• Fondaparinux (Arixtra) is an anti-Xa inhibitor.

• Fondaparinux has been found to be noninferior to enoxaparin in reducing the risk of ischemic events.

• Fondaparinux significantly lowers major bleeding events compared with enoxaparin.

• Fondaparinux currently does not have FDA approval for this indication.

• Indications for therapy are as follows:

• Enoxaparin or UFH in combination with aspirin and clopidogrel should be given to all patients unless contraindicated.

• Enoxaparin or fondaparinux is continued for the duration of hospitalization, up to 8 days, or until a PCI procedure is completed.

• Enoxaparin may be superior to heparin in patients with UA or NSTEMI.

• For patients with increased risk of bleeding and not undergoing angiography, fondaparinux is preferred.

• Fondaparinux is not recommended if a patient is going to undergo PCI.

Lipid-lowering therapy

• Lipid-lowering therapy is used in patients with documented or suspected CAD or CHD risk equivalents and LDL ≥ 100 mg/dL: target LDL < 100 mg/dL.

• In high-risk patients, target LDL < 70 mg/dL may be appropriate.

• Lipid-lowering medications should be initiated prior to discharge.

11-6. Acute Myocardial Infarction: STEMI


More than 85% of all MIs occur by thrombus formation precipitated by atherosclerotic plaque rupture. Aggregated platelets after plaque rupture can serve as a substrate for thrombus propagation, leading to formation of an occlusive thrombus. This complete occlusion results in abrupt and persistent ischemia that clinically manifests as STEMI. Left untreated, occlusion of the coronary arteries can lead to sudden cardiac death. See

Table 11-3 for a comparison of STEMI and NSTEMI.


Patients with right ventricular (RV) wall infarction should be managed similarly to LV infarction except that NTG, diuretics, and other preload reducing agents should be avoided in RV wall MIs because these patients are dependent on preload.

RV MI may require volume loading with IV fluids to maintain preload and cardiac output.

Symptoms differ from an LV wall MI in that an RV wall MI can cause hypotension, elevated jugular venous pressure, and cardiogenic shock because of inadequate filling of the LV.

[Table 11-3. STEMI versus UA or NSTEMI]

Ventricular remodeling

Ventricular remodeling can occur as a result of myocardial necrosis and may continue for months following MI. It leads to activation of the neurohormonal and renin-angiotensin systems that will ultimately affect ventricular shape, size, and function. It precipitates chronic changes in ventricular volume, ventricular dilation, hypertrophy, and eventually heart failure. ACEIs, ARBs, and β-blockers and the combination of hydralazine plus nitrates reduce the progression of ventricular remodeling. A combination of ACEI plus ARB has been noted to cause more frequent side effects, such as renal dysfunction and hyperkalemia. Aldosterone blockade has been proven beneficial in the post-MI setting with LV dysfunction with eplerenone.


Mortality factors

• The highest risk of death from MI is generally within the first 48 hours.

• Anterior MIs usually involve a larger area of the myocardium than do inferior MIs, and thereby have a higher mortality.

• An important prognostic factor following MI is LV function because heart failure is one of the most serious complications of MI.

• Large anterior wall MIs, LV dysfunction, and complex ventricular ectopy carry the highest mortality rate post-MI.

• Early identification and risk stratification can reduce mortality following MI.

Predictors of death

• High troponin concentration correlates with higher death rates in STEMI and NSTEMI.

• Predictors of death within 30 days post-MI include age greater than 70 years, hypertension, atrial fibrillation, tachycardia, large infarct size, previous MI, and female.

• Lower-risk patients include those younger than 71 years of age with an LVEF ≥ 40%.

• Patients who continue to have frequent ventricular arrhythmias following MI are at high risk of sudden cardiac death.


Symptoms are similar to UA/NSTEMI. Atypical presentation is common in women, elderly patients, and those with diabetes.


Two of the following three criteria must be met:

• Chest pain generally lasting for more than 30 minutes

• ECG changes such that there is ST-segment elevation of 0.1 mV in two contiguous limb leads or 0.1-0.2 mV elevation in at least two contiguous precordial leads

• With respect to cardiac isoenzymes, troponin T or I elevation

Goals of Therapy in Acute MI

• Limit infarct size.

• Reverse myocardial ischemia and thereby salvage myocardium.

• Minimize complications.

• Reduce mortality.

Pharmacologic Management of STEMI

Morphine, oxygen, nitrates, and aspirin

Refer to see Table 11-2 for information about morphine, oxygen, nitrates, and aspirin therapy.

The following points apply to nitrate use in STEMI:

• If chest pain is not relieved by sublingual nitroglycerin, intravenous nitrates may be used for the first 24-48 hours in all patients with acute MI who do not have hypotension, bradycardia, tachycardia, or suspected RV infarctions. Nitrates salvage ischemic myocardium by relaxation of vascular smooth muscles in veins, arteries, and arterioles.

• Nitrates demonstrate insignificant reductions in mortality beyond 48 hours. Use is reserved for those patients with large acute MIs, persistent chest discomfort, heart failure, hypertension, or persistent pulmonary congestion.

• Cautions and contraindications: Carefully titrate in patients with inferior wall MI because of its frequent association with RV infarction. Such patients are especially dependent on adequate RV preload to maintain cardiac output and can experience profound hypotension during nitrate administration.

• Do not administer nitrates to patients who have received a phosphodiesterase inhibitor for erectile dysfunction within the last 24 hours (48 hours for tadalafil).

Reperfusion therapy

Primary PCI

(See Section 11-7 for more information.)

• PCI is an intervention designed to reopen a partially or completely occluded coronary artery to reestablish blood flow.

• The goal is door-to-balloon time of < 90 minutes.

• Mechanical reperfusion (percutaneous transluminal coronary angioplasty, or PTCA, with coronary stenting) has been shown to be more successful than fibrinolysis.

• In patients who receive a stent, dual antiplatelet therapy with aspirin and clopidogrel therapy should be added to the regimen, as in UA and NSTEMI, and continued for at least 12 months.

Fibrinolytic therapy

• Fibrinolytic therapy is also known as thrombolytic therapy.

• Fibrinolytic therapy improves myocardial O2 supply, limits infarct size, and decreases mortality.

• Controversy exists about one lytic agent's superiority over another.

• A door-to-needle time of < 30 minutes is an important goal.

• Signs of successful reperfusion include relief of chest pain, resolution of ST-segment changes, and reperfusion arrhythmias, usually ventricular in nature.

• Fibrinolytic therapy is unsuccessful in approximately 22-30% of patients.

• Indications for therapy are as follows:

• ST-segment elevation is > 1 mm in two or more contiguous leads or left bundle branch block is present (obscuring ST observational changes).

• Presentation is within 12 hours of symptom onset.

• The patient has no contraindications to fibrinolytic therapy and indications for therapy.

• In patients age > 75 years, fibrinolytic therapy may be useful and appropriate.

• Fibrinolytic therapy can be used in STEMI when time to therapy is 12-24 hours if chest pain is ongoing.

• It should not be used if the time to therapy is > 24 hours and the ischemic pain is resolved.

• It should not be used for ST depression.

• Long-term therapy (e.g., 1 year) with clopidogrel plus aspirin is reasonable in patients who receive fibrinolytic therapy.

Antithrombotic and anticoagulant therapy

• Indications for UFH, enoxaparin, and fondaparinux therapy are as follows:

• IV UFH is administered with selective fibrinolytics (e.g., alteplase, reteplase, and tenecteplase) for the prevention of recurrent coronary thrombosis for a minimum of 48 hours.

• IV UFH can be administered with nonselective fibrinolytic agents (e.g., streptokinase) in patients at high risk for systemic emboli (large or anterior MI, atrial fibrillation, previous emboli, or known LV thrombus).

• Enoxaparin can be used as an alternative to UFH in patients receiving fibrinolytic therapy, with different dosing strategies dependent on age and renal function.

• Patients not treated with a thrombolytic and without contraindications can be treated with IV UFH or LMWH (enoxaparin 1 mg/kg subcutaneous bid or fondaparinux 2.5 mg IV followed by 2.5 mg subcutaneous daily) for at least 48 hours for UFH and for up to 8-9 days for the latter agents.

• Two studies support the benefits of clopidogrel 75 mg daily in addition to aspirin in STEMI patients regardless of whether they receive fibrinolytic therapy or no reperfusion therapy. In patients < 75, it is reasonable to administer a 300 mg loading dose of clopidogrel.

β-adrenergic blockade

• Early β-blocker use post-MI reduces infarct size, cardiovascular mortality, reinfarction rate, and nonfatal cardiac arrests and increases probability of long-term survival.

• Oral β-blocker therapy should be administered within the first 24 hours to patients who do not have contraindications.

• It is reasonable to administer early IV β-blocker therapy to STEMI patients who are hypertensive and without any contraindications (e.g., heart failure, low output state, risk for cardiogenic shock, bradycardia, blocks, hypotension).

• Late administration of a β-blocker (at least 24 hours after MI) improves LV diastolic filling and reduces risk of recurrent MI and death.

• Indications for therapy are as follows:

• Early therapy: β-blockers should be given to all patients with acute MI who can be treated within 12 hours of STEMI, regardless of administration of concomitant thrombolytic therapy. IV or oral treatment should be started as soon as possible in all patients within 12-24 hours after onset of symptoms if no contraindications exist.

• Late therapy: β-blockers should be given to all patients without a clear contraindication to β-blocker therapy. Treatment should begin within a few days of the event (if not initiated earlier) and should be continued indefinitely.

Glycoprotein IIb/IIIa Inhibitors (GPIs)

• Trials evaluating the role of platelet GPI in STEMI in combination with full- and half-dose fibrinolytic agents have shown a more complete reperfusion at the price of higher bleeding rates, especially in elderly patients.

• Abciximab administered early before primary PCI reduces the incidence of combined death, MI, and recurrent ischemia in patients with STEMI.

Inhibition of the RAA system: ACEIs, ARBs, and aldosterone inhibitors

• The primary goal is to limit postinfarction LV dilatation and hypertrophy so that pump function is preserved or improved. ACEIs attenuate the remodeling process and thereby slow the progression to heart failure post-MI.

• Benefits of ACEIs are clearly most pronounced in patients with evidence of ventricular dysfunction (either objective evidence such as LVEF ≤ 40% or subjective evidence such as heart failure symptoms).

• Other high-risk patients (previous MI, heart failure, and anterior MI without thrombolytic therapy) have shown marked benefit from ACEIs.

• Recent studies of ACEI therapy suggest acute treatment should be given to patients considered at higher risk because of a history of hypertension, diabetes, or previous MI and should be continued indefinitely.

• An ARB can be used for those patients who are intolerant of an ACEI and have either clinical or radiological signs of heart failure or an LVEF of ≤ 40%.

• Aldosterone blockade (eplerenone, spironolactone) should be prescribed post-STEMI in those patients already on an ACEI with an LVEF ≤ 40% and with either symptomatic heart failure or diabetes.

• Aldosterone blockers should be avoided in patients with renal dysfunction (serum creatinine ≥ 2.5 mg/dL in men or ≥ 2.0 in women) or hyperkalemia (potassium > 5 mEq/L).

• Indications for therapy are discussed in Section 11-5.

Lipid lowering

Indications for therapy are discussed in Section 11-5.

Calcium channel blockers

• Verapamil or diltiazem should be used only with continuing ischemia when β-blockers are either contraindicated or used at maximum dose with nitrates.

• Verapamil or diltiazem should not be used in patients with left ventricular systolic dysfunction, AV block, hypotension, or bradycardia.


• Warfarin is recommended in patients with indications for anticoagulation (e.g., LV thrombus, atrial fibrillation, extensive wall motion abnormalities).

• In patients requiring triple therapy with aspirin, clopidogrel, and warfarin, an INR range of 2.0-2.5 is recommended with low-dose aspirin (75-81 mg daily).

• Use of warfarin in combination with aspirin, clopidogrel, or both is associated with an increased risk of bleeding and should be carefully monitored.

Treatment of ventricular fibrillation post-MI

• The risk of ventricular fibrillation (VF) is at highest during the first 4 hours post-MI and then declines sharply.

• Prophylactic antiarrhythmic use has been shown to increase all-cause mortality when used to prevent VF; it is not recommended.

• Amiodarone may be used if patients experience VF or hemodynamically compromising ventricular tachycardia following MI.

11-7. Revascularization

Percutaneous Coronary Intervention Procedures

Procedure types include balloon angioplasty (PTCA), coronary stenting, and ablative technologies (laser, atherectomy).

Primary PCI is a very effective method for reestablishing coronary perfusion and is suitable for at least 90% of patients. Primary PCI should be performed as quickly as possible with the goal of a medical contact-to-balloon or door-to-balloon time of 90 minutes or less. Primary PCI is favored over fibrinolytic therapy because PCI-treated patients experience lower short-term mortality rates and fewer nonfatal reinfarctions and hemorrhagic strokes than those treated with fibrinolytic therapy.

Facilitated PCI refers to a strategy of planned immediate PCI after an initial pharmacologic regimen, such as full-dose fibrinolytics, GPIs, or another pharmacologic regimen. Rescue PCI refers to the use of PCI when fibrinolytic therapy has failed.

Revascularization is not preferred in women with low-risk features.

Potential complications of invasive PCI include problems with arterial access site, technical complications, acute vessel closure, restenosis, and acute renal failure secondary to nephrotoxic dye.

Bare Metal Stents and Drug-Eluting Stents

Restenosis is the loss of 50% or more of the diameter of the in-stent lumen at the site of an initially successful intervention; it usually occurs within the first 3-6 months.

Drug-eluting stents (DES) were introduced in 2003 and have the principal advantage of reducing restenosis over angioplasty alone and bare metal stents (BMS).

Pharmacologic agents, such as sirolimus, paclitaxel, zotarolimus, and everolimus, are embedded in the steel stent and released over time.

DES have reduced the rate of restenosis to less than 5%.

Anticoagulation during PCI

Anticoagulation is mandatory because the vessel manipulation during PCI is inherently thrombogenic.

Possible agents include the following:

• UFH has traditionally been the mainstay of therapy.

• Studies have shown that the direct thrombin inhibitor bivalirudin may be as effective as heparin but with less bleeding. The use of bivalirudin seems to eliminate the need for GPIs when an appropriate clopidogrel loading dose is given.

• Enoxaparin use during PCI can be challenging. Dosing is determined based on the last administered dose of enoxaparin. If the last subcutaneous dose was administered within 8 hours, no additional enoxaparin needed; if the last dose was administered after 8-12 hours, 0.3 mg/kg IV should be given.

• Fondaparinux is not recommended during PCI secondary to catheter thromboses. If PCI is planned, an alternative anticoagulant should be used.

Antiplatelet therapy during PCI

Aspirin and clopidogrel

Clopidogrel in combination with aspirin is used to reduce in-stent thrombosis and is used for at least 1 month with BMS, ideally up to 12 months, and a minimum of 12 months with DES for patients not at high risk for bleeding.

The dose of aspirin is 162-325 mg daily for at least 1 month after BMS, 3 months after sirolimus-eluting stents, and 6 months after paclitaxel-eluting stents. With the newer DES, everolimus, and zotarolimus, a minimum of 75 mg of aspirin daily is acceptable after PCI. After the initial poststent period is complete, the dose of aspirin can be reduced to 75-162 mg daily.

Glycoprotein IIb/IIIa inhibitors

Although similar effects have been noted with each of the GPIs, the timing of PCI should be determined before an agent is selected.

GPIs are administered before or during PCI for patients who are troponin-positive or have other high-risk features.

Use abciximab or eptifibatide if PCI is anticipated soon after presentation (< 4 hours).

GPIs can be omitted if bivalirudin is used in place of UFH and at least 300 mg clopidogrel was administered at least 6 hours prior.

Coronary Artery Bypass Graft Surgery

CABG is indicated in patients with multivessel disease with LV dysfunction or significant disease of a major coronary vessel that is not amenable to PCI.

Clopidogrel should not be used for a minimum of 5 days prior to CABG to reduce the risk of bleeding.

11-8. Primary Prevention: Risk Factor Modification


The majority of the causes of cardiovascular disease are known and modifiable. Therefore, risk factor screening should begin at age 20 with the hope that all adults know the levels and significance of risk factors as routinely assessed by their primary care provider.

Nonmodifiable Risk Factors


• Men > 45

• Women > 55 (or those who had an early hysterectomy regardless of age)


Higher risk in African American males and females than in Caucasian males and females

Family history

• Father or brother with a coronary event before age 55

• Mother or sister with a coronary event before age 65

Modifiable Risk Factors

• Smoking

• Hypertension

• Hyperlipidemia

• Diabetes

• Metabolic syndrome

• Obesity

• Physical inactivity

• Alcohol consumption

Pharmacologic Therapy


The Eighth American College of Clinical Pharmacy Evidence-Based Clinical Practice Guidelines on Antithrombotic and Thrombolytic Therapy (Chest Guidelines) recommends that ASA (75-325 mg/day) be considered for individuals who have at least moderate risk (based on age and cardiac risk factor profile with a > 10% risk of cardiac event over 10 years) for CAD and who are without contraindications.

The American College of Cardiology and American Heart Association (AHA) recommend doses of 75-162 mg/day in persons at higher risk of cardiovascular disease (especially those with a 10-year risk of CHD > 10%).

The American Diabetes Association recommends ASA therapy to prevent cardiovascular events in most patients with diabetes who are > 40 years of age and have no contraindications to ASA.

The recommendation for aspirin use for primary prevention is stronger in men than in women, and aspirin can be prescribed based on risk profile (stroke versus MI) and age:

• For women < 65 years of age who are at risk for ischemic stroke and low bleeding risk, 75-100 mg/day can be preventive.

• For women > 65 years of age who are at risk for ischemic stroke or MI and low bleeding risk, 75-100 mg/day can be preventive.

ACEIs and ARBs

In the HOPE trial, ramipril demonstrated effectiveness in reducing the risk of MI, stroke, and death from cardiovascular causes in patents at high risk of a major cardiovascular event. ACEIs may be used as protective agents.

The European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) similarly showed perindopril to be beneficial in patients with evidence of coronary heart disease but without heart failure and has led to the increased use of ACEIs in patients with vascular disease but without heart failure or LV dysfunction.

Results from the Prevention of Events with Angiotensin Converting Enzyme (PEACE) inhibition trial suggest that low-risk patients with CAD who are receiving maximal therapy with β-blockers, aspirin, and lipid-lowering therapies do not gain clinically significant benefit from the addition of trandolapril 4 mg daily.

Chronic ACEI therapy may be most beneficial in high-risk patients (uncontrolled hyperlipidemia, hypertension, smoking, proteinuria, vascular disease).

Lipid lowering

Consider lipid lowering in all patients at risk for a coronary event.


There is no consistent evidence with vitamin E or other antioxidant therapy to recommend its use for primary prevention of heart disease.

Nonpharmacologic Therapy for IHD

Smoking cessation

Smoking cessation is one of the most important risk-modifying behaviors. Evidence suggests that the best adherence to a cessation program combines pharmacotherapy with behavioral modification.

A wide range of smoking cessation aids (prescription and nonprescription) products is available.

Nicotine replacement alone is not an effective management strategy for smoking cessation. Nicotine combined with bupropion has been the most successful.


Diets low in saturated fat and high in fruits, vegetables, whole grains, and fiber are associated with a reduced risk of cardiovascular disease. With respect to omega-3 fatty acids: the AHA Dietary Guidelines recommends inclusion of at least two servings of fish per week (particularly fatty fish). Food sources high in alpha-linolenic acid (e.g., soy bean, canola, walnut, and flaxseed oil and walnuts and flaxseeds) are also recommended.


Regular aerobic physical activity increases a person's capacity for exercise. Exercise plays a role in both primary and secondary prevention of cardiovascular disease.

Current guidelines from the U.S. Centers for Disease Control and Prevention and National Institutes of Health recommend that Americans should accumulate at least 30 minutes of moderate-intensity physical activity on most, preferably all, days of the week to prevent risk of chronic disease in the future. The Institute of Medicine recommends 60 minutes of physical activity per day.

Weight loss

Weight loss can reduce blood pressure, lower blood glucose levels, and improve blood lipid abnormalities. A goal of 5% to 10% of body weight loss is associated with decreased morbidity and mortality.

Pharmacotherapy used for weight loss should be reserved for (a) those with a body mass index exceeding 30 and (b) those with a body mass index exceeding 25 plus other risk factors for comorbid diseases.

Alcohol consumption

Lowest cardiovascular mortality occurs in those who consume one or two drinks per day. People with no alcohol consumption have higher total mortality than those drinking one or two drinks per day.

In the absence of alcohol-related illnesses, one or two drinks per day in males and one alcoholic drink per day in females may be considered for high-risk patients. A drink equivalent amounts to a 12-ounce bottle of beer, a 4-ounce glass of wine, or a 1.5-ounce shot of 80 proof spirits.

A general increase in alcohol consumption at the population level is not recommended.

11-9. Pharmacology

Anti-ischemic Drug Therapy


The use of β-blockers in anti-ischemic drug therapy is discussed in Chapter 8.


Mechanism of action

• Organic nitrates are prodrugs that must be transformed to exert pharmacological effect.

• NTG leads to denitration of the nitrate, liberation of NO, guanylyl cyclase stimulation, the conversion of guanosine triphosphate to cGMP, and vasodilation.

• NO also reduces platelet adhesion and aggregation and affects endothelial function and vascular growth.


• Oral: Isosorbide dinitrate and NTG undergo extensive first-pass metabolism when given orally. Mononitrate does not; it is completely bioavailable.

• IV: IV use achieves the highest concentrations. Usually, IVs are used for only 24 hours to avoid developing tolerance.

• SL tablet or spray for immediate-release: Unlike tablets, spray does not degrade when exposed to air. The half-life is 1-5 minutes regardless of route.



Table 11-4 for information about doses.

Monitoring parameters

Blood pressure and heart rate should be monitored.

Adverse drug reactions

Adverse drug reactions to nitrate are described in

Table 11-5.

Drug-drug interactions

Nitrate drug-drug interactions are described in

Table 11-6.

Drug-disease interactions

• Glaucoma

• Intraocular pressure may increase.

• Use with caution in patients with glaucoma.

• Hypertrophic obstructive cardiomyopathy

• Severe aortic stenosis: Can cause hypotension and syncope


• If sildenafil and vardenafil are used within 24 hours.

• If tadalafil is used within 48 hours.

• Hypersensitivity to nitrates can occur.

Patient instructions and counseling

• General instructions:

• Avoid alcohol consumption.

• May cause dizziness; use caution when driving or engaging in hazardous activities until drug effect is known.

• When standing from a sitting position, rise slowly to avoid an abrupt drop in blood pressure.

• Notify physician of acute headache, dizziness, or blurred vision.

• Instructions for sublingual tablets:

• Keep tablets in their original container.

• Dissolve tablet under the tongue. Lack of tingling does not indicate a lack of potency.

[Table 11-4. Pharmacologic Properties and Doses of Nitrates]

[Table 11-5. Nitrate Adverse Reactions]

[Table 11-6. Nitrate Drug-Drug Interactions]

• Take one tablet at the first sign of chest pain. If chest pain is unrelieved, seek emergency medical attention.

• Instructions for translingual spray:

• Spray under tongue or onto tongue.

• Hold spray nozzle as close to the mouth as possible and spray medicine onto or under the tongue.

• Do not inhale the spray, use near heat or open flame, or use while smoking.

• Close mouth immediately after spraying.

• Avoid eating, drinking, or smoking for 5-10 minutes.

• If the pain does not go away after one spray, seek emergency medical attention.

• Instructions for transmucosal tablets:

• Place tablet between cheek and gum. Do not chew tablet; allow it to dissolve over a 3- to 5-hour period.

• Touching the tablet with the tongue or hot liquids may increase release of the medication.

• Instructions for ointment:

• Measure the correct amount using the papers provided with the product.

• Use papers for the application, not fingers.

• Apply to the chest or back.

• Instructions for transdermal patches:

• Tear the wrapper open carefully. Never cut the wrapper or patch with scissors. Do not use any patch that has been cut by accident.

• Apply to a hairless area and rotate sites to avoid irritation. Be sure to remove the old patch before applying a new one.

• Do not put the patch over burns, cuts, or irritated skin.

• Remove the patch approximately 12-14 hours after placing it on every day. This prevents tolerance to the beneficial effects of NTG.

• Used patches may still contain residual medication; use caution when disposing around children and pets.

• Store the patches at room temperature in a closed container, away from heat, moisture, and direct light. Do not refrigerate.

• Instructions for sustained-release tablets:

• Take at the same time each day as directed.

• Do not chew or crush tablets or capsules.

Calcium channel blockers

The use of calcium channel blockers in anti-ischemic drug therapy is discussed in Chapter 8.

Ranolazine (Ranexa)

Mechanism of action

The mechanism of action of ranolazine not clearly understood, but appears to inhibit the late Na current (INa), preventing Ca overload and ultimately blunting the effects of ischemia by improving myocardial function and perfusion.


• Initiate at 500 mg po bid and titrate to a maximum dose of 1 g po bid as tolerated.

• Take without regard to meals. Do not crush, break, or chew tablet.

Monitoring parameters

• Monitor anginal symptoms.

• Perform baseline and follow-up ECGs to evaluate QT interval.

• Monitor BP regularly in patients with severe renal insufficiency.

Adverse drug reactions

Adverse reactions to ranolazine are described in

Table 11-7.

Drug-drug interactions

Drug-drug interactions are described in

Table 11-8.


• Use with strong CYP3A inhibitors.

• Use with CYP3A inducers.

• Use in patients with clinically significant hepatic impairment.

Patient instructions and counseling

• Ranolazine is not for acute anginal symptoms.

• Notify physician if you take any other medications, including over-the-counter medications.

[Table 11-7. Ranolazine Adverse Drug Reactions]

[Table 11-8. Ranolazine Drug-Drug Interactions]

• Notify physician if you have any history or family history of QTc prolongation or congenital long-QT syndrome or if you are receiving drugs that prolong the QTc interval, such as antiarrhythmic agents, erythromycin, and certain antipsychotics (thioridazine, ziprasidone).

• Do not take drugs that are strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir) or strong inducers of CYP3A (e.g., rifampin, carbamazepine, phenytoin).

• Notify physician if you take drugs that are moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin) or P-glycoprotein inhibitors (e.g., cyclosporine).

• Ranolazine can be taken with or without meals.

• Ranolazine should be swallowed whole; do not crush, break, or chew tablets.

• Ranolazine may cause dizziness or lightheadedness; therefore, notify physician if you experience fainting spells, and know how you react to this drug before operating heavy machinery.

Inhibition of the RAA system

See Chapter 9 for information about angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone blockers.

Antiplatelet Drug Therapy


Mechanism of action

Aspirin blocks prostaglandin synthesis, which prevents the formation of thromboxane A2.


• At the onset of chest pain: 160-325 mg chewed and swallowed

• Maintenance dose: 75-162 mg for life, except immediately post PCI, when a maintenance dose of 75-325 mg daily is appropriate depending on the type of stent received

• Monitoring parameters: signs of bleeding, renal function, tinnitus

Adverse drug reactions

Adverse reactions to aspirin are described in

Table 11-9.

Drug-drug interactions

Antiplatelet agents, anticoagulants, nonsteroidal anti-inflammatory drugs (NSAIDs), and celecoxib may all increase the risk of bleeding if used in combination with ASA.

Drug-disease interactions

• Peptic ulcer disease (PUD).

• Other active bleeding.

• Aspirin may cause gastric ulceration.

• An enteric-coated tablet is recommended.

Patient instructions and counseling

• Avoid additional over-the-counter products containing ASA, NSAIDs, or salicylate ingredients without the direction of a physician.

[Table 11-9. Aspirin Adverse Reactions]

• Patients who received a stent or were treated medically after an acute coronary event will need the combination of clopidogrel and aspirin.

• Notify physician of dark, tarry stools, persistent stomach pain, difficulty breathing, unusual bruising or bleeding, or skin rash.

• Do not crush an enteric-coated product.


Mechanism of action

Thienopyridines block adenosine diphosphate (ADP)-mediated activation of platelets by selectively and irreversibly blocking ADP activation of the glycoprotein IIb/IIIa complex.



• Loading dose: 300-600 mg orally

• Maintenance dose:

• 75 mg daily combined with aspirin for at least 1 month and ideally up to 12 months in patients who were treated medically and did not undergo cardiac cath

• 75 mg daily combined with aspirin for at least 1 month with BMS, ideally up to 12 months, and a minimum of 12 months with DES for patients not at high risk for bleeding

• 75 mg daily for life in patients who cannot tolerate aspirin


• Loading dose: 500 mg orally

• Maintenance dose: 250 mg bid

Monitoring parameters


Monitor for signs of bleeding.


Monitor CBC with differential every 2 weeks for the first 3 months of therapy, liver function tests periodically, and for signs of bleeding.

Discontinue ticlopidine if the absolute neutrophil count drops to < 1,200 or platelet count drops to < 80,000.

Adverse drug reactions

Adverse reactions to thienopyridine are described in

Table 11-10.

Drug-drug interactions

Drug-drug interactions are described in

Table 11-11.

Drug-disease interactions

PUD or other active bleeding

[Table 11-10. Thienopyridine Adverse Reactions]


• Hypersensitivity to an individual product

• Active bleeding (e.g., gastrointestinal or intracranial hemorrhage)

• Severe liver disease

• Neutropenia, thrombocytopenia

Patient instructions and counseling

• All patients who received a stent or were treated medically after an acute coronary event will need the combination of clopidogrel and aspirin.

• Avoid additional ASA, salicylates, and NSAID products unless under the direction of a physician.

• Notify physician for unusual bleeding or bruising; blood in the urine, stool, or emesis; skin rash; or yellowing of the skin or eyes.

• Do not stop taking without discussing with physician.

• Discontinue clopidogrel at least 5 days prior to CABG.

Glycoprotein IIb/IIIa receptor inhibitors

Mechanism of action

• Blockade of the glycoprotein IIb/IIIa receptor prevents fibrinogen binding, thus inhibiting platelet aggregation, the final common pathway for platelet aggregation.

Properties of individual agents


Table 11-12 for properties of GPIs.

[Table 11-11. Thienopyridine Drug-Drug Interactions]

[Table 11-12. Pharmacologic Properties of Glycoprotein IIb/IIIa Receptor Inhibitors]

Indications and doses

Table 11-13 provides information about indications and doses.

Monitoring parameters

Hematocrit and hemoglobin, platelet count, PT and aPTT, and activated clotting time (with PCI) should be monitored.

Adverse drug reactions

Adverse drug reactions include bleeding, thrombocytopenia, and allergic reaction from repeated exposure (abciximab).

Drug-drug interactions

Antiplatelet agents, anticoagulants, NSAIDs, and celecoxib may all increase the risk of bleeding if used in combination with GPIs.

Drug-disease interactions

PUD or other active bleeding


• Active bleeding

• Platelet count < 100,000

• History of intracranial hemorrhage, neoplasms, AV malformations, or aneurysm

• History of stroke within the past 30 days or any history of hemorrhage stroke

• Severe hypertension (BP > 180/110 mm Hg)

• Major surgery within past 6 weeks

• Dialysis dependent (eptifibatide only)



Mechanism of action

Heparin enhances the action of antithrombin III, thereby inactivating thrombin and preventing the conversion of fibrinogen to fibrin.


• UA and NSTEMI: 60-70 units/kg (maximum 5,000 units) IV bolus, 12-15 units/kg/h (maximum 1,000 units/h) infusion titrated to an aPTT range of 50-70 seconds

• STEMI (in combination with tPA, rPA, or tenecteplase): 60 units/kg (maximum 4,000 units) IV bolus, 12 units/kg/h (maximum 1,000 units/h)

[Table 11-13. Indications and Doses of the Glycoprotein IIb/IIIa Receptor Inhibitors]

   infusion titrated to an aPTT range of 50-70 seconds for 48 hours

Monitoring parameters

Monitor aPTT, PT, platelet count, hemoglobin and hematocrit, signs of bleeding, and activated clotting time (with PCI).

Adverse drug reactions

Bleeding, thrombocytopenia, hemorrhage, epistaxis, allergic reactions, and osteoporosis may occur.

Protamine can be used to reverse the effects of heparin; 1 mg of protamine neutralizes 100 units of heparin.

Drug-drug interactions

Antiplatelet agents, anticoagulants, NSAIDs, and celecoxib may all increase the risk of bleeding if used in combination with UFH. Switching from heparin to LMWH may increase the risk of bleeding and has been reported to cause death.

Drug-disease interaction

PUD or other active bleeding


• History of heparin-induced thrombocytopenia

• Severe thrombocytopenia

• Active bleeding

• Suspected intracranial hemorrhage

LMWH (enoxaparin) and factor Xa inhibitors (fondaparinux)

Mechanism of action

The mechanism of action is similar to that of heparin; however, these drugs are stronger inhibitors of thrombin formation through inhibition of factor Xa.


Properties are described in

Table 11-14.


• Enoxaparin (Lovenox):

• UA and NSTEMI: 1 mg/kg SC q12h (creatinine clearance < 30 mL/min: 1 mg/kg SC q24h)

• STEMI with fibrinolytic therapy: 30 mg IV then, 1 mg/kg SC q12h (creatinine clearance < 30 mL/min: 1 mg/kg SC q24h); for patients > 75 years of age, eliminate the IV bolus and give 0.75 mg/kg SQ q12h

• Fondaparinux (Arixtra), as an alternative to UFH:

• UA and NSTEMI: For patients in whom a conservative strategy is selected over an invasive strategy, 2.5mg SC daily up to 9 days

• STEMI (with or without fibrinolytics): 2.5 mg IV, then SC daily up to 9 days; not recommended if patient undergoing primary PCI

[Table 11-14. Properties of Low Molecular Weight Heparin versus Unfractionated Heparin]

Monitoring parameters

Serum creatinine, platelet count, hemoglobin and hematocrit, anti-Xa levels (optional), and signs of bleeding should be monitored. It is not necessary to monitor aPTT or PT with LMWH or direct Xa inhibitors.

Adverse drug reactions

Adverse reactions include bleeding, thrombocytopenia, hemorrhage, and epistaxis.

Drug-drug interactions

Antiplatelet agents, anticoagulants, NSAIDs, and celecoxib may all increase the risk of bleeding if used in combination with LMWH.

Switching from LMWH to UFH may increase the risk of bleeding and has been reported to cause death.

Drug-disease interactions

PUD or any active bleeding


Patients with recent or anticipated epidural or spinal anesthesia are at risk of hematoma and subsequent paralysis.


• Severe thrombocytopenia

• Active bleeding

• Suspected intracranial hemorrhage

Thrombolytic Therapy

Mechanism of action

Thrombolytic therapy acts either directly or indirectly to activate or convert plasminogen to plasmin to lyse a formed clot. The conversion of plasminogen to plasmin activates the body's natural thrombolytic-fibrinolytic system, which lyses the clot and releases fibrin degradation products.


Thrombolytic doses are given in

Table 11-15.

Monitoring parameters

CBC, ECG, aPTT, signs of bleeding, and signs of reperfusion should be monitored.

Adverse drug reactions

Adverse reactions include bleeding, intracranial hemorrhage (< 1%), stroke (< 2%), and epistaxis.

Drug-drug interactions

Antiplatelet agents, anticoagulants, NSAIDs, and celecoxib may all increase the risk of bleeding if used in combination with thrombolytics.



• Any prior intracranial hemorrhage

• Known structural cerebrovascular lesion

• Ischemic stroke within 3 months, except acute ischemic stroke within 3 hours

• Known intracranial neoplasm (primary or metastatic)

• Active internal bleeding or bleeding diathesis (does not include menses)

• Suspected aortic dissection

• Significant closed head or facial trauma within 3 months

[Table 11-15. Thrombolytic Doses]

Relative contraindications

• Severe uncontrolled hypertension (BP > 180/110 mm Hg)

• History of prior ischemic stroke greater than 3 months, dementia, or known intracerebral pathology not covered in contraindications

• Current use of anticoagulants in therapeutic doses (INR > 2-3)

• Traumatic or prolonged (> 10 min) cardiopulmonary resuscitation or major surgery (< 3 weeks)

• Noncompressible vascular punctures

• Recent (within 2-4 weeks) internal bleeding

• For streptokinase, prior exposure (especially within 5 days to 2 years) or prior allergic reaction

• Pregnancy

• Active peptic ulcer

• History of chronic severe hypertension

11-10. Key Points

• Angina is a syndrome described as discomfort or pain in the chest, arm, shoulder, back, or jaw. Angina is frequently worsened by physical exertion or emotional stress and is usually relieved by sublingual NTG. Patients with angina usually have CAD.

• Anginal symptoms are caused by a decrease in O2 supply because of reduced blood flow.

• The goals for treating stable angina are to prevent death, reduce symptoms, and improve quality of life.

• Aspirin has been shown to decrease the incidence of MI, adverse cardiovascular events, and sudden death in patients with CAD.

• β-blockers are first-line therapy for treatment of angina in patients with or without a history of MI if there are no contraindications.

• Patients prescribed nitrates for treatment of angina need to be counseled on their appropriate use.

• Ranolazine is a novel antianginal medication that does not affect BP or HR. It can be used as initial therapy or in combination with other antianginal medications.

• Upon hospital presentation with UA, NSTEMI, or STEMI, initial therapy for all patients is morphine, oxygen, nitroglycerin, and aspirin. If there are no contraindications, all patients should be given aspirin therapy for life.

• The first-line anti-ischemic therapy for the treatment of UA and NSTEMI is a β-blocker. If chest pain continues or a β-blocker is contraindicated, a calcium channel blocker or long-acting nitrate should be considered, in that order.

• In addition to aspirin therapy for life, clopidogrel should be administered to all patients who undergo stent replacement for at least 1 month after BMS but ideally up to 12 months and for at least 12 months after DES stents. Long-term treatment with clopidogrel may be beneficial in patients with established vascular disease. Clopidogrel should be withheld for 5-7 days prior to surgery to reduce the risk of major bleeding.

• Any of the available glycoprotein IIb/IIIa agents should be considered in patients undergoing a PCI procedure. In patients without a planned PCI, eptifibatide or tirofiban can be used for medical treatment.

• All patients presenting with UA or NSTEMI should receive anticoagulation with UFH or LMWH.

• STEMI differs from UA and NSTEMI in that a totally occlusive clot causes damage across the entire thickness of the myocardial wall. The damage to the heart is more extensive with STEMI and ECG changes differ.

• Primary reperfusion (either PCI or fibrinolytic therapy) is the main treatment strategy for STEMI, with primary PCI being preferred.

• Ventricular remodeling (post-MI) resulting after myocardial damage can be slowed and possibly reversed by using long-term ACE inhibition and β-blockade (use ARBs as alternative to ACEIs and hydralazine + nitrates in combination with ACEIs in African American patients with LV dysfunction).

• Secondary prevention of MI should include aspirin, β-blockers, ACEIs, and statin therapy (to achieve an LDL goal of < 100 mg/dL; < 70 mg/dL in high-risk patients) in all patients who have no contraindications.

• Aldosterone blockade should be considered post-STEMI in patients with an LVEF ≤ 40% and either symptomatic heart failure or diabetes.

11-11. Questions

Questions 1-3 refer to this case:

Mr. Smith is a 66-year-old white male who presented to his local physician with complaints of chest pain. He described the pain as sharp, aching, and non-radiating. The pain, which he has had for the past few weeks, has occurred mainly during his daily walk and is usually relieved when he stops to rest.

Past medical history: hypertension, PUD, asthma, CAD

Family history: Father died of a stroke at 86; mother died at age 82 with diabetes mellitus and heart failure; sister died of MI at 52

Social history: Smokes 1 pack per day × 40 years; drinks alcohol socially 1-2 times a week


• Proventil MDI 2 puffs prn

• Flovent 44 mcg 2 puffs bid

• Prilosec 20 mg daily

• Aspirin 75 mg daily

• HCTZ 25 mg daily

Vital signs: BP 148/92; HR 82; RR 18; height 72²; weight 200 lbs

Labs: (fasting) total cholesterol 226 mg/dL; TG 110 mg/dL; HDL 38 mg/dL; LDL 166 mg/dL; Chem 12-within normal limits

ECG: Normal (patient currently pain free)

Cath 6 years ago: Minimal two-vessel disease


How would you classify Mr. Smith's chest pain?

A. Unstable angina

B. Stable angina

C. Variant angina

D. Silent ischemia




Considering Mr. Smith's situation, which of the following would be the most appropriate therapeutic intervention?

A. SL NTG prn

B. Propranolol

C. Tirofiban

D. Verapamil and SL NTG prn

E. Atenolol, amlodipine, and SL NTG



What additional medication should be considered for Mr. Smith?

A. Ticlopidine

B. Atorvastatin

C. Clopidogrel

D. Eptifibatide

E. Reteplase



Which of the following effects on myocardial oxygen demand do β-blockers not cause?

A. Decreased HR

B. Decreased BP

C. Decreased contractility

D. Peripheral vasodilation

E. Decreased conduction through the AV node



Which of the following statements is true regarding the use of calcium channel blockers in IHD?

A. Amlodipine and felodipine reduce MVO2 by decreasing conduction through the AV node.

B. Calcium channel blockers should be used as first-line therapy in patients with stable angina.

C. Newer-generation dihydropyridines like nifedipine immediate-release are safe in the treatment of IHD.

D. Calcium channel blockers can be used in combination with β-blockers to attenuate the effect of increased sympathetic tone that some dihydropyridines may cause.

E. The combination of verapamil and metoprolol in a patient with reduced LV systolic function is safe and well tolerated by most patients.



Which of the following counseling points should be made to a patient being prescribed SL NTG?

I. Take at the same time each day as directed.

II. Keep tablets in their original container.

III. Take at the first sign of chest pain; if chest pain is unrelieved, seek emergency medical attention.

A. III only

B. I, II, and III

C. I and III only

D. I and II only

E. II and III only



Which of the following is not considered a potential cardiovascular benefit of ACEIs in IHD?

A. They reduce the incidence of MI.

B. They reduce the incidence of cardiovascular death and stroke in patients at high risk for vascular disease.

C. Agents with high tissue ACE inhibition have been proven to be superior and provide better protection.

D. ACE inhibitors should be used in all stable angina patients with known CAD who also have diabetes.

E. ACE inhibitors have shown greater benefit post-MI in higher-risk patients.



Which of the following drugs do not appear to interact with an exercise tolerance test (ETT)?

A. Nitrates

B. Digoxin

C. Atenolol

D. Flecainide

E. Clopidogrel



Ideal properties for a β-blocker in the treatment of UA or NSTEMI include which of the following?

A. Available as an IV product, cardioselectivity

B. Low lipophilicity, has intrinsic sympathomimetic activity (ISA)

C. Has ISA, cardioselectivity

D. Cardioselectivity, low lipophilicity, does not have ISA

E. Noncardioselective, high lipophilicity



Nitrates decrease oxygen demand through the following mechanism(s):

I. Peripheral vasodilation

II. Arterial vasodilation

III. Decreasing contractility

A. I only

B. II only

C. I and II only

D. II and III only

E. I, II, and III



The possible benefits of LMWH over UFH include all of the following except

A. predictable response.

B. ease of administration.

C. no recommended routine monitoring.

D. stronger affinity for thrombin.

E. no renal adjustment necessary.



Which of the following β-blockers has ISA activity?

A. Tenormin

B. Sectral

C. Inderal

D. Lopressor

E. Coreg



Which of the following medications is contraindicated within 24 hours of a nitrate?

A. Metoprolol

B. Quinapril

C. Verapamil

D. Sildenafil

E. Felodipine



Which of the following is the preferred narcotic to relieve chest pain after the use of SL NTG?

A. Meperidine

B. Oxycodone

C. Morphine

D. Hydromorphone

E. Fentanyl


Questions 15 and 16 refer to this case:

J. O. is a 54-year-old male who presents to the hospital with crushing substernal chest pain and radiation to his left arm. Past medical history is significant for hypertension, COPD, and gout. J. O. has a history of smoking × 30 years and occasionally consumes alcohol. Vital signs on admission include BP 170/85; pulse 72; RR 18; temp 97. Before admission, the patient was taking enteric-coated aspirin 81 mg daily; Combivent inhaler 2 puffs qid; Tiazac 240 mg daily; allopurinol 300 mg daily.

Allergies: sulfa

Lab/diagnostic tests:

• ECG: ST-segment depression, T-wave changes

• Troponin: T-positive × 3

• Ejection fraction: < 35%

• LDL: 135 mg/dL



• Heart failure


What is the preferred β-blocker for this patient?

A. Propranolol

B. Carvedilol

C. Labetalol

D. Metoprolol

E. Nadolol



All of the following therapies should be considered in this patient except

A. reteplase.

B. clopidogrel.

C. enalapril.

D. simvastatin.

E. unfractionated heparin.


Questions 17 and 18 refer to this case:

S. D. is a 56-year-old female who presents to the local emergency room complaining of crushing, substernal chest pain × 3 hours, which has been unrelieved by SL NTG. PMH is pertinent for hypertension, T2DM, hypercholesterolemia, and metabolic syndrome. Heart rate and rhythm are regular, and no S3 or S4 sounds are present. Vital signs include BP 184/119, HR 100, and RR 32/min. S. D.'s ECG shows ST-segment elevation > 1 mm in leads II, III, and aVF. She is immediately admitted to the chest pain center and started on oxygen.


Which of the following criteria for the diagnosis of MI are present in S. D.?

A. Chest pain symptoms are relieved by SL NTG.

B. ST-segment elevation is greater than 1 mm in two or more noncontiguous leads.

C. Chest pain symptoms with ECG changes are consistent with MI or necrosis.

D. S. D. does not meet the criteria for MI based on the above presentation because myocardial enzymes have not been evaluated.

E. Negative enzymes rule out MI.



Which of the following agents should be administered to S. D.?

A. tPA 100 mg IV over 90 minutes

B. IV magnesium

C. Prophylactic lidocaine

D. Metoprolol 5 mg IV

E. Diltiazem 240 mg po



What medications should a patient who is post-MI with preserved LVEF receive as discharge therapy?

A. Aspirin, clopidogrel, diltiazem, and simvastatin

B. Aspirin, metoprolol, enalapril, atorvastatin, and SL NTG

C. Clopidogrel, metoprolol, enalapril, and simvastatin

D. Morphine, aspirin, SL NTG, and clopidogrel

E. Morphine, SL NTG, aspirin, and oxygen



The anticoagulant effect of unfractionated heparin requires the binding to which plasma cofactor?

A. Thrombospondin

B. Antithrombin III

C. Plasminogen

D. Factor XIIa

E. Factors II, VII, IX, and X


Question 21 refers to this case:

S. P. is a 45-year-old marathon runner. He presents to the emergency department with complaints of chest pain during his morning run. His father died of a myocardial infarction at age 48. His past medical history is positive for angina, hyperlipidemia, and hypertension. His current medications include aspirin, pravastatin, nifedipine, and clonidine. His electrocardiogram is consistent with acute ischemia. His HR is 52 and BP is 170/100. CBC and Chem-7 are within normal limits.


All of the following interventions are appropriate for S. P. except

A. enoxaparin 1 mg/kg SC bid.

B. IV metoprolol followed by po metoprolol.

C. nitroglycerin SL prn and IV drip titrated to pain and blood pressure.

D. continue aspirin.

E. morphine if NTG does not control the pain.



Which one of the following agents is not indicated in the setting of STEMI when pharmacologic reperfusion is the planned strategy?

A. Eptifibatide


C. Aspirin

D. tPA

E. Metoprolol



Which of the following agents would not be administered at the same time as heparin?

A. tPA

B. Reteplase

C. Eptifibatide

D. TNKase

E. Streptokinase



Which of the following statements about the GPIs is not true?

A. Abciximab, eptifibatide, and tirofiban are all administered as a bolus followed by a continuous infusion.

B. It is possible to experience an allergic reaction after repeated exposure to abciximab.

C. Eptifibatide, tirofiban, and abciximab can all be reversed by a platelet infusion.

D. Tirofiban and eptifibatide are renally eliminated; therefore, dosage adjustment is required for patients with renal dysfunction.

E. Abciximab, eptifibatide, and tirofiban are all indicated as adjuncts to PCI.


11-12. Answers


B. Angina is considered stable if symptoms have been occurring for several weeks without worsening, it lasts < 30 minutes, and it is relieved by rest or SL NTG.



D. This regimen will help control his angina without β2-blocking effects in this asthmatic patient, as well as lower his BP. SL NTG will be useful for acute attacks. A is not the best answer because this patient also needs a medication to lower his BP. B is incorrect because propranolol is not β1-selective and could worsen his asthma. C is incorrect because GPIs are not indicated in stable angina. E is incorrect; combination therapy is not recommended as first-line therapy and should be considered only when initial treatment with a β-blocker is not successful.



B. Mr. Smith has an elevated LDL with known heart disease, and he needs to be treated to a goal LDL of < 100 mg/dL (consider LDL < 70 mg/dL). A and C are incorrect; these antiplatelet agents are not indicated for treating stable angina unless a patient cannot tolerate aspirin. D and E are incorrect because GPIs and thrombolytics are not indicated in stable angina.



D. Unlike nitrates or calcium channel blockers, β-blockers do not cause peripheral vasodilation.



D. The increased sympathetic tone caused by some dihydropyridines can lead to a reflex tachycardia, which would be detrimental in an IHD patient. Therefore, using a β-blocker to block this effect would be desirable. A is incorrect; unlike verapamil or diltiazem, the dihydropyridines do not decrease conduction through the AV node. B is incorrect; CCBs are not indicated as first-line therapy unless a patient has a contraindication to a β-blocker. C is incorrect because immediate release nifedipine can lead to increased side effects if not combined with a β-blocker. E is incorrect because both verapamil and metoprolol can lead to worsening systolic function, and used in combination, they would be unsafe.



E. SL NTG should be kept in the original amber bottle, because exposure to light or extreme temperatures will cause it to lose potency. III is correct, and patients should be counseled to take one tablet and seek medical attention if chest pain is not relieved. I is incorrect; SL NTG is used on a prn basis and should not be taken at the same time each day.



C. It has not been proven that so-called tissue ACEIs are better than other ACE inhibitors.



E. Clopidogrel, or Plavix, does not have any pharmacologic interaction with an ETT. Digoxin can cause an abnormal exercise-induced ST depression in approximately 30% of healthy patients. β-blockers and vasodilators can alter hemodynamic response to BP and should be withdrawn gradually 4-5 half-lives before ETT. Nitrates can attenuate angina and flecainide may cause exercise-induced ventricular tachycardia.



D. Ideally, a β-blocker used for the treatment of UA or NSTEMI would have β1-receptor selectivity, no ISA, and low lipophilicity. Being available as an intravenous agent is not an advantage because β-blockers should be initiated orally to avoid adverse effects. β1-receptor selectivity would reduce the chance for bronchospasm, and low lipophilicity would reduce the neurological side effects. β-blockers with ISA reduce heart rate to a lesser degree than non-ISA β-blockers, thus producing a smaller decrease in oxygen demand.



C. Nitrates are vasodilators acting on both arteries and in the periphery, thereby decreasing preload and afterload. Regarding anti-ischemic therapy, only β-blockers and nondihydropyridine calcium channel blockers reduce contractility.



E. Renal adjustment is necessary with LMWH. UFH does not require dosage adjustment in renal patients and is preferred to LMWH in patients with a creatinine clearance < 30 mL/min. LMWH does appear to have advantages over UFH in ease of administration, its affinity to thrombin (stronger than UFH), its more predictable response, and the fact that it does not require monitoring.



B. β-blockers with ISA activity include Sectral (acebutolol), Cartrol (carteolol), Levatol (penbutolol), and Visken (pindolol). Tenormin (atenolol), Inderal (propranolol), Lopressor (metoprolol), and Coreg (carvedilol) do not have ISA activity.



D. Sildenafil use is contraindicated within 24 hours of a nitrate. β-blockers (metoprolol), ACEIs (quinapril), and calcium channel blockers (verapamil and felodipine) can be safely combined with nitrates.



C. Morphine has vasodilator properties, thereby decreasing both preload and afterload, which decreases oxygen demand. In addition, morphine lowers heart rate by relieving pain and anxiety. If a true morphine allergy exists, meperidine may be used as an alternate agent. Oxycodone, hydromorphone, and fentanyl are not recommended for the treatment of anginal pain.



D. With the patient's history of COPD, a β-blocker with β1-receptor selectivity is preferred. The only agent with β1-selectivity in this list is metoprolol. All of the remaining agents are nonselective. In addition, metoprolol would be an appropriate β-blocker to use in this patient with heart failure.



A. Reteplase is a thrombolytic agent, which does not have a role in the treatment of NSTEMI. Thrombolytic therapy is indicated for the treatment of STEMI. Clopidogrel and GPI (eptifibatide) should be considered in all patients with NSTEMI with or without PCI. Eptifibatide and tirofiban can be used in patients who are medically managed; abciximab is reserved for patients with a scheduled PCI procedure. Lipid-lowering therapy with an HMG-CoA reductase inhibitor (e.g., simvastatin) should be initiated in this patient because his LDL is > 130 mg/dL. This patient has a clear indication for an ACEI (enalapril) because of his ejection fraction of < 40%. An anticoagulant should be started on presentation; options include UFH or LMWH.



C. A is incorrect. Although chest pain unrelieved by NTG is a diagnostic criterion for MI, two criteria must be present before the diagnosis can be made. B is incorrect because ST-segment elevation > 1 mm must be found in two or more contiguous leads. S. D. has both chest pain symptoms and ECG changes that are consistent with myocardial infarction. C is correct because she meets two of the three criteria for diagnosing MI. S. D. does not have positive enzymes, which would meet the third diagnostic criteria. D is incorrect because positive enzymes do not have to be present for the diagnosis of MI to be made (as is the case with S. D.).



D. One of the relative contraindications to fibrinolytic therapy is severe uncontrolled hypertension (BP > 180/110 mm Hg). A is not appropriate in this patient with BP of 184/119 mm Hg. Routine use of magnesium post-MI is not recommended and should be reserved for patients with hypomagnesemia. No labs were given for S. D., so answer B is not appropriate at this time. Prophylactic lidocaine has been shown to increase all-cause mortality and is not recommended in the early management of STEMI for prevention of VF. Therefore, C is incorrect. β-blockers reduce the incidence of ventricular arrhythmias, recurrent ischemia, reinfarction, infarct size, and mortality in patients with STEMI. Because S. D. does not have any contraindications to β-blockade, D is the correct choice. E, calcium channel blockers, do not have a role in STEMI when a β-blocker can be given.



B. ACEIs, β-blockers, aspirin, statin therapy, and SL NTG should be given to all patients without contraindications post-MI. Clopidogrel can be combined with aspirin and can be continued for at least 12 months regardless of whether the patient underwent PCI. Answers A and C, which include clopidogrel, are incorrect, however, because A omits β-blockade, and C omits aspirin therapy. Calcium channel blockers can be given if a patient has contraindications to β-blockade, but it is not recommended as first-line treatment. Answers D and E are incorrect because ACE inhibition and β-blockade are omitted. Answer E would be a correct choice for the immediate treatment of someone who presents with STEMI, but not as discharge therapy.



B. Heparin's anticoagulant effect requires binding to antithrombin (previously antithrombin III), and that binding converts antithrombin from a slow, progressive thrombin inhibitor to a very rapid inhibitor of thrombin and factor Xa.



B. One of the contraindications to β-blockade is a HR < 55 bpm. Because S. P. has an HR of 52 bpm, the only inappropriate therapy of the choices given would be B. Enoxaparin, NTG, morphine, and aspirin are all therapies that should be continued.



A. Glycoprotein IIb/IIIa inhibition is still controversial in the setting of STEMI, especially when a fibrinolytic agent is administered. The role of GPIs in STEMI is rapidly evolving, and trials to date in combination with full- and half-dose fibrinolytic agents have shown a more complete reperfusion at the price of higher bleeding rates. At this point, there is no formal recommendation on using eptifibatide or another GPI in STEMI.



E. A GPI should be administered with heparin, and therefore C is not the correct answer. Combination of UFH with streptokinase is less desirable because it is a nonspecific fibrinolytic, and UFH may increase the risk of bleeding because of streptokinase's long half-life. Therefore, answer E is the correct choice. Heparin should be administered for at least 48 hours with the other lytic choices to reduce risk of reocclusion.



C. The only GPI that is reversed by a platelet infusion is abciximab. All of the remaining selections are true statements. All of the available GPI agents are administered as a bolus and infusion. Abciximab is a monoclonal antibody; therefore, it is possible to develop an allergic reaction upon rechallenge. Only two GPIs are renally eliminated: eptifibatide and tirofiban. All of the agents are indicated as adjunct to PCI, so E is true.


11-13. References

American Diabetes Association. Aspirin therapy in diabetes. Diabetes Care. 2004;27(suppl 1): S72-73.

Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines update for the management of patients with unstable angina/non-ST-segment elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction). J Am Coll Cardiol. 2007;50:1-57. Available at:

Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). 2004. Available at:

Antman EM, Hand M, Armstrong PW, et al. 2007 Focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2008;51:210-47. Available at:

Becker RC, Meade TW, Berger PB, et al. The primary and secondary prevention of coronary artery disease. Chest. 2008;133:776S-814S.

Dagenais GR, Yusuf S, Bourassa MG, et al. Effects of ramipril on coronary events in high-risk persons: Results from the Heart Outcomes Prevention Evaluation Study. Circulation. 2001;104:522-26.

Deepak LB, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354: 1706-17.

Dobesh PP, Trujillo TC. Ranolazine: A new option in the management of chronic stable angina. Pharmacotherapy. 2007;27:1659-76.

Fox KM, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-8.

Fraker TD Jr, Fihn SD, writing on behalf of the 2002 Chronic Stable Angina Writing Committee. 2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina. J Am Coll Cardiol. 2007;50: 2264-74. Available at:

Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for the Management of Patients with Chronic Stable Angina). 2002. Available at:

Grundy SM, Cleeman JI, Berz NB, et al. Implications of recent clinical trials for the national cholesterol education program adult treatment panel III guidelines. Circulation. 2004;110:227-39.

King SB III, Smith SC Jr., Hirshfeld JW Jr, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: (2007 Writing Group to Review New Evidence and Update the 2005 ACC/AHA/SCAI Guideline Update for Percutaneous Coronary Intervention). J Am Coll Cardiol. 2008;51:172-209. Available at:

Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics—2009 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119:e21-181.

Mehta SR, Yusuf S, Peter RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE study. Lancet. 2001;358:527-33.

Meister FL, Stringer KA, Spinler SA, et al. Thrombolytic therapy for acute myocardial infarction. Pharmacotherapy. 1998;18:686-98.

Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007; 115:1481-501.

Patrono C, Baigent C, Hirsh J, Roth G. Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133:199S-233S.

PEACE trial investigators. Angiotensin-converting enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:2058-68.

Ridker PM, Cook NR, Lee I-M, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352:1293-304.

Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update. Circulation 2006;113:2363-72.

Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol. 2006;47:e1-121.

Spinler SA, de Denus S. Acute coronary syndromes. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:249-78.

Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. JAMA. 2002;288:2411-20.

Summary of the Second Report of the National Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-97.

Talbert RL. Ischemic heart disease. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:217-47.

Trujillo TC, Dobesh PP. Traditional management of chronic stable angina. Pharmacotherapy. 2007;27: 1677-92.

Wong GC, Giugliano RP, Antman EM. Use of low molecular-weight heparins in the management of acute coronary artery syndromes and percutaneous coronary intervention. JAMA. 2003;289:331-42.