63

In the ISIS-2 trial, the greatest reduction in mortality occurred in the elderly

subgroup. There are no controlled trials in which fibrinolytic therapy has increased

mortality in the elderly. However, in a high-risk cohort of elderly female patients

(older than 75 years, <67 kg), the ASSENT investigators demonstrated that TNK was

associated

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p. 253

with lower rates of major bleeding and intracerebral hemorrhage compared to tPA. Another potential strategy to reduce intracranial hemorrhage risk is a reduced

dose of fibrinolytic. The Strategic Reperfusion Early after Myocardial Infarction

(STREAM) trial evaluated prehospital fibrinolytic therapy and reduced the dose of

TNK by 50% in patients ≥75 years of age.

63 The intracranial hemorrhage rate was

reduced to 0.5% and coronary patency rates were similar when compared to patients

<75 years of age who received full-dose TNK. It is also important to ensure

appropriate dosage adjustments are made for concomitant medications according to

age (e.g., enoxaparin), weight (e.g., prasugrel), and renal function (e.g., enoxaparin

and fondaparinux).

β-Blockers

CASE 13-1, QUESTION 15: The physician wishes to write a prescription for a β-blocker. What are the

benefits of administering a β-blocker to P.H.? Should it be given as IV therapy or started as oral therapy a few

days after the infarction?

β-Blockers offer significant benefits to the MI patient. Several large trials gave IV

β-blockers (up to 24 hours after symptom onset) followed by oral therapy; other

studies used oral therapy alone beginning days after the infarction. Early IV

administration appears to be most beneficial, with a reduction in mortality of about

25% in the first 2 days when the results of these trials are pooled. However, late oral

therapy alone, initiated up to 21 days after an MI in the β-Blocker in Heart Attack

Trial, was also associated with a substantial reduction in mortality (around 10%).

5

Early IV administration of propranolol, metoprolol, timolol, and atenolol has been

studied. Typically, metoprolol is used in the acute setting because of its β1

selectivity, ease of dosing and administration, and weight of evidence. Oral

carvedilol, a nonselective β- and α-blocker, has been used in the peri-infarction

period, specifically in patients with LV dysfunction. In the Carvedilol Post-Infarction

Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial, carvedilol

6.25 mg twice daily titrated to 25 mg twice daily reduced all-cause and

cardiovascular mortality as well as recurrent nonfatal MI.

64

It is important to tailor β-blockade therapy for each patient, as evidenced in the

COMMIT trial.

65

In this study, patients were randomized to placebo or metoprolol

(up to 15 mg IV of metoprolol, then oral 200 mg metoprolol succinate daily) within

24 hours of AMI. Although metoprolol reduced reinfarction and ventricular

fibrillation rates compared with placebo, it was associated with a significant

increase in cardiogenic shock. Patients with hemodynamic instability at

randomization were at greatest risk of early cardiogenic shock associated with

metoprolol. Given these concerns, oral β-blockers are generally preferred. If the

patient is hypertensive or having ongoing ischemia, then IV metoprolol tartrate (5 mg

IV every 5 minutes as tolerated up to three doses) can be considered (see Table 13-

2). For all other patients without contraindications, oral metoprolol tartrate 25 to 50

mg every 6 to 12 hours should be initiated. Doses should be titrated on the basis of

BP and heart rate. If a patient has transient cardiac decompensation or is at risk for

cardiogenic shock during the acute infarction period, early IV β-blockers should be

withheld. The patient’s condition may be observed for a few days; if it stabilizes,

oral therapy is initiated and titrated slowly. The ACC/AHA guidelines highlight the

importance of an individualized approach, but do provide guidance on suggested

dosing recommendations for both acute and long-term use.

In our case, P.H.’s situation is complicated by his history of intermittent pulmonary

problems. In deciding whether to attempt use of β-blockers in patients with

pulmonary disease, one must determine the nature of the pulmonary problem (i.e.,

reactive airway disease). It also would be helpful to determine P.H.’s need for

routine use of β-agonists to help quantify the severity of his disease. By history, P.H.

does not use β-agonist bronchodilators routinely. No history is given regarding his

pulmonary function tests or the degree of reversibility of his airway disease with

bronchodilators. β1

-selective antagonists are the drugs of choice in these patients, but

at higher doses (e.g., metoprolol doses > 100 mg/day), the relative β1

-selectivity may

be lost. A patient would need to experience significant worsening of the pulmonary

disease to justify avoiding β-blockers. A better history of P.H.’s pulmonary problems

should be obtained. If they are minor and as he has experienced an uncomplicated

MI, P.H. may be a candidate for early therapy with metoprolol to reduce chest pain

as well as decrease the risk of reinfarction and arrhythmias.

Nitroglycerin

CASE 13-1, QUESTION 16: Despite SL NTG, P.H. continues to have chest discomfort. Would he benefit

from IV NTG?

Because P.H. is exhibiting refractory ischemic discomfort despite receiving SL

and topical nitrates, symptomatic management with IV NTG is indicated. NTG

lowers the LV filling pressure and systemic vascular resistance, thereby reducing

myocardial oxygen consumption and myocardial ischemia. At lower doses (<50

mcg/minute), IV NTG preferentially dilates the venous capacitance vessels, which

leads to a decrease in LV filling pressure. For patients who have signs of pulmonary

congestion, IV NTG is of particular value.

CASE 13-1, QUESTION 17: How should IV NTG be administered to P.H.? How should it be monitored?

A continuous infusion of NTG is delivered in a controlled manner, starting with 5

to 10 mcg/minute, which is then increased by an additional 5 to 10 mcg/minute every

5 to 10 minutes if needed. Many cardiologists routinely give patients an infusion of

NTG for the first 24 to 48 hours after an AMI. Increasing doses may be required

during this period to maintain the desired hemodynamic effect owing to tolerance that

occurs from prolonged nitrate exposure. However, if more than 200 mcg/minute is

needed to achieve the desired response, another vasodilator may be needed. NTG is

typically administered in combination with fibrinolytic agents in patients who require

relief from myocardial ischemia.

Patients with an inferior or right ventricular infarct often develop hypotension

(mean BP < 80 mm Hg) when given NTG. P.H.’s BP should be monitored closely

during this infusion. After starting NTG, we would expect to see his BP decline; the

pulse rate may or may not increase. The NTG dose should be titrated to relieve pain

while avoiding symptomatic hypotension. In patients with evidence of HF, NTG can

reduce LV filling pressure (preload), as well as improve orthopnea and pulmonary

congestion. However, excessive doses of IV NTG can reduce LV filling pressure to

excess, and potentially decrease cardiac output. The systolic BP should be

maintained to at least 90 mm Hg. Once P.H.’s chest pain is controlled, he may be

transitioned to either an oral agent or his transdermal delivery system increased.

With either choice, a nitrate-free interval should be maintained (see Chapter 12,

Chronic Stable Angina).

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p. 254

TREATMENT FOR UNSTABLE ANGINA OR NON–

ST SEGMENT ELEVATION MYOCARDIAL

INFARCTION

Invasive Versus Ischemia-Guided Strategy

CASE 13-2

QUESTION 1: J.W. is a 65-year-old man who presents to the ED with chest tightness and shortness of

breath. He gives a history of similar symptoms the previous day that lasted 20 minutes. He was given aspirin

325 mg, intranasal oxygen, PO metoprolol tartrate, and started on an IV NTG infusion, which was increased to

80 mcg/minute; at that time, his BP was 130/60 mm Hg, and his heart rate was 88. His ECG revealed ST

segment depression in the anterior leads. His shortness of breath was relieved, but he still complained of chest

tightness. His past medical history includes hypertension for which he takes hydrochlorothiazide 25 mg daily.

His mother died of a heart attack at age 62. He has smoked a pack of cigarettes per day for the past 30 years.

Laboratory values include the following:

Na, 135 mEq/L

K, 4.0 mEq/L

Cl, 100 mEq/L

CO2

, 20 mEq/L

BUN, 15 mg/dL

SCr, 1.1 mg/dL

Glucose, 100 mg/dL

Mg, 2 mEq/L

CK-MB fraction, 1% (normal, 0%–5%)

Troponin I-Ultra, 0.05 ng/mL (normal, <0.02 ng/mL)

Hgb, 14 g/dL

Hct, 44%

Plt, 288 × 10

3

/mm

3

Based on his symptoms and ECG, the diagnosis is presumed UA. Should J.W. receive an invasive or

ischemia-guided strategy for management of his NSTE-ACS?

Although J.W. has negative biomarkers after 24 hours from his first episode of

chest pain suggesting UA, the presence of new ST segment depression may prompt

the clinician to choose an early invasive approach within 24 hours (see Fig. 13-6). If

however, the patient is not at high or intermediate risk, then the invasive approach

may be delayed and performed within 25 to 72 hours. A TIMI score would also be

helpful to risk stratify the patient. J.W. has a score of 4 indicating a 19.9% risk at 14

days of all-cause mortality, new or recurrent MI, or severe recurrent ischemia

requiring urgent revascularization. When risk stratifying, scores of 0 to 2, 3 to 4, and

5 to 7 represent low, moderate, and high risk for death or repeat MI at 14 days. So,

based on his TIMI risk score, he is moderate risk. As an alternative, calculating a

GRACE score would indicate 137 points representing an 11% risk of in-hospital

death or MI and a 19% risk at 6 months. An ischemia-guided strategy might be

selected based on patient or clinician preference in the absence of high-risk features

such as elevated biomarkers. In this approach, pharmacotherapy would be initiated

followed by a noninvasive stress evaluation. If J.W. were to have elevated cardiac

biomarkers during his presentation, his diagnosis would be NSTEMI and an early

invasive (within 24 hours) approach may be preferred. If during his hospitalization,

J.W. were to experience any recurrent ischemia, arrhythmias, or signs and symptoms

of HF, he would proceed directly to angiography and undergo possible PCI.

Anticoagulant Therapy

CASE 13-2, QUESTION 2: What anticoagulant regimen should J.W. receive?

The ACC/AHA guidelines recommend beginning anticoagulant therapy for all

patients (without contraindications) with NSTE-ACS as soon as possible. The

guidelines recommend one of four agents: UFH, enoxaparin, fondaparinux, or

bivalirudin (approved only for patients managed according to an invasive strategy).

Table 13-2 summarizes the dosing and contraindications for each of these agents.

In NSTE-ACS, UFH has been associated with lower rates of death or MI than

aspirin alone.

1 Despite its limitations, UFH is preferred if the patient is to undergo

CABG because of its rapid clearance. For an invasive strategy, the guidelines give a

higher level of evidence for enoxaparin but do warn about an increase in bleeding.

1

When choosing an anticoagulant, renal function, bleeding risk, and concomitant

therapy should be considered.

Data supporting LMWHs in this setting come from several studies. In the Efficacy

and Safety of Subcutaneous Enoxaparin (ESSENCE) study, enoxaparin (1 mg/kg SQ

twice daily) was compared with UFH (5,000 units IV bolus followed by continued

infusion titrated to an aPTT of 55 to 86 seconds).

66 The composite outcome of death,

MI, or recurrent angina at 14 days was reduced by 20% in the enoxaparin group. This

benefit was maintained for 1 year.

In the Superior Yield of the New Strategy of Enoxaparin, Revascularization and

Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial, 9,978 high-risk NSTE-ACS

patients were randomized to enoxaparin (1 mg/kg SQ twice daily) or weight-based

UFH (60 units/kg bolus followed by 12 units/kg/hour adjusted to an aPTT 1.5 to 2

times control) before undergoing an early invasive strategy.

67 Enoxaparin was found

to be as efficacious as UFH in reducing 30-day all-cause mortality or nonfatal MI but

was associated with a significant risk of major bleeding (p = 0.008). Bleeding was

especially problematic in those patients who crossed over from one treatment to the

other during the trial.

In the TIMI-11B trial, enoxaparin (30 mg IV bolus followed by 1 mg/kg SQ twice

daily for 8 days) compared with UFH (70 units/kg bolus followed by 15

units/kg/hour for 3 to 8 days) reduced the composite end point of death, MI, or need

for urgent revascularization.

68 The benefit of enoxaparin is greatest for high-risk

subgroups such as those with ST segment changes, elevated troponins, and a high

TIMI risk score.

1

Finally, enoxaparin has been compared with fondaparinux. In the OASIS-5 trial,

NSTE-ACS patients were randomized to fondaparinux (2.5 mg SQ daily) or

enoxaparin (1 mg/kg SQ twice daily) for a mean of 6 days and evaluated at 9 days for

the primary end point of death, MI, or refractory ischemia.

69 There was no difference

between groups for the primary end point; however, compared with enoxaparin,

fondaparinux had a significantly lower incidence of major bleeding at 9 days (p <

0.001) and a greater reduction in mortality at 30 days (p = 0.05). Based on these

data, the guidelines give preference to fondaparinux compared with other

anticoagulants for patients who are at an increased risk of bleeding and being treated

with an ischemia-guided (conservative medical management) strategy. If

fondaparinux is used for a patient undergoing PCI, an additional anticoagulant with

factor IIa activity such as UFH is needed.

1

Bivalirudin is given a Class I recommendation in the guidelines. In the Acute

Catheterization and Urgent Intervention Triage

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p. 255

Strategy (ACUITY) trial, patients with NSTE-ACS managed with an early

invasive strategy were randomly assigned to receive either UFH (or enoxaparin) plus

a GP IIb/IIIa inhibitor, bivalirudin plus a GP IIb/IIIa inhibitor, or bivalirudin alone.

70

No differences in the primary end point (composite of death, MI, unplanned

revascularization for ischemia, and major bleeding at 30 days) were observed

between the group receiving UFH plus a GP IIb/IIIa inhibitor and the group receiving

bivalirudin plus a GP IIb/IIIa inhibitor. However, compared with those receiving

UFH plus a GP IIb/IIIa inhibitor, the 30-day composite of ischemia or major bleeding

was significantly lower for those receiving bivalirudin alone. This difference was

attributed to reduced major bleeding with bivalirudin.

The Unfractionated Heparin versus Bivalirudin In Primary Percutaneous Coronary

Intervention (HEAT-PPCI) trial was a head to head comparison of bivalirudin versus

UFH.

71 Patients who underwent emergent PCI were randomly assigned to receive

either UFH or bivalirudin. At 28 days, the primary efficacy outcome of ≥1 major

adverse cardiac events was significantly lower in the UFH group. When the

individual components were evaluated, there was no difference in all-cause mortality

or cerebrovascular accident. The driving factors favoring heparin were new MI or

reinfarction and additional unplanned target lesion revascularization. The majority of

these cases were related to stent thrombosis in the bivalirudin group (0.9% vs. 3.4%,

p = 0.001). Major and minor bleeding events did not differ between the two groups.

Because J.W. is receiving an invasive strategy for his NSTE-ACS and he has

adequate renal function, enoxaparin, UFH, or bivalirudin could be initiated and

continued until the end of PCI.

Antithrombotic Therapy

CASE 13-2, QUESTION 3: What oral antithrombotic medications should be considered for J.W.?

For both an ischemia-guided and invasive strategy, aspirin along with a P2Y12

antagonist (loading with maintenance dose) should be added as soon as possible to

anticoagulant therapy unless the patient is to proceed to CABG. For an invasive

strategy, prasugrel or ticagrelor can be considered in lieu of clopidogrel. The 2014

ACC/AHA guidelines recommend ticagrelor as the preferred agent (Class IIa).

Prasugrel should only be used in patients undergoing PCI as long as they are not at

high risk of bleeding complications.

1

The use of clopidogrel in NSTE-ACS was evaluated in two studies.

72,73

In the

Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial,

patients with NSTE-ACS were randomized to placebo plus aspirin (75 to 325 mg) or

clopidogrel (300 mg, immediately followed by 75 mg daily) plus aspirin.

72 The

composite of cardiovascular death, MI, or stroke was significantly reduced with

clopidogrel. However, compared with placebo, an increase in major and minor

bleeding was seen. On the basis of these data, clopidogrel with aspirin should be

administered immediately on admission and continued ideally for 1 year in patients

with ACS.

1

The PCI-Clopidogrel as Adjunctive Reperfusion Therapy (PCI-CLARITY) study

was a planned subanalysis (n = 1,863) of the CLARITY-TIMI 28 study (see Case 13-

1, Question 9) that evaluated the effects of pretreatment with aspirin plus

clopidogrel, compared with aspirin plus placebo, in patients undergoing PCI with

coronary artery stenting.

74 Compared with placebo, pretreatment with clopidogrel

significantly reduced the incidence of cardiovascular death, MI, or stroke as well as

recurrent MI or stroke before PCI with no significant excess in TIMI major or minor

bleeding.

CASE 13-2, QUESTION 4: What loading dose should he receive and when should he receive it? What about

his maintenance dose?

A loading dose of 600 mg of clopidogrel in patients undergoing PCI achieves

greater platelet inhibition with fewer low responders and decreases the incidence of

major cardiac events compared with a loading dose of 300 mg.

1 A 300-mg

clopidogrel loading dose provides adequate antiplatelet activity in 6 hours whereas a

600-mg clopidogrel loading dose provides antiplatelet activity in 2 hours. Even after

a loading dose, clopidogrel requires several hours to be metabolized to its active

metabolite. The current guidelines prefer 600 mg because of a greater, more rapid,

and more consistent degree of platelet inhibition. Patients undergoing PCI who have

previously received a loading dose of 300 mg of clopidogrel and are on a 75-mg

daily maintenance dose should receive another 300-mg loading dose. Data do not

exist on additional loading doses for patients currently receiving maintenance doses

of prasugrel or ticagrelor.

Prasugrel has been evaluated in patients with ACS undergoing PCI. In the

Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–

Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 study, patients with

moderate to high-risk ACS, 26% of whom had STEMI, were randomized to prasugrel

(60 mg loading dose followed by 10 mg daily) or clopidogrel (300 mg loading dose

followed by 75 mg daily).

75 All patients received aspirin (75 to 162 mg daily). The

primary outcome of death from cardiovascular causes, nonfatal MI, or nonfatal stroke

occurred in 9.9% of patients receiving prasugrel and in 12.1% of patients taking

clopidogrel (p < 0.001). However, prasugrel was associated with a significant

increase in TIMI—major, fatal, and life-threatening bleeding. A post hoc analysis

found three subgroups that did not benefit from prasugrel: patients with a history of

stroke or TIA, age of 75 years or older, or body weight less than 60 kg. Patients with

at least one of these risk factors exhibited a higher rate of bleeding.

76 The Food and

Drug Administration (FDA) recommends a 5-mg (rather than 10-mg) maintenance

dose be considered for those patients weighing less than 60 kg, even though this dose

has not been studied.

77

In the Study of Platelet Inhibition and Patient Outcomes (PLATO) trial, patients

with ACS, with or without ST segment elevation were randomized to receive

ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300 to

600 mg loading dose, then 75 mg daily). Compared to clopidogrel, ticagrelor

demonstrated a 16% reduced rate of mortality from MI, vascular causes, or stroke (p

< 0.001) without an increase in the rate of major bleeding but an increased rate in

CABG-related bleeding (p = 0.03).

78 However, the lowest 1-year rates of

cardiovascular death, MI, or stroke were noted in patients with ACS treated with

ticagrelor and maintenance low-dose aspirin (≤100 mg/day), whereas the highest

rates occurred in those treated with ticagrelor and high-dose aspirin (>300 mg/day).

79

Based on these data, the maintenance dose of aspirin should not exceed 100 mg/day.

80

When compared with clopidogrel, prasugrel and ticagrelor are more potent,

exhibit a lower incidence of stent thrombosis, have fewer drug–drug interactions, and

lack variable response based on pharmacogenomics (refer to Chapter 12, Chronic

Stable Angina, about responders and nonresponders to clopidogrel). However, many

providers have been concerned with the higher risk of bleeding. In the case of J.W.,

clopidogrel, prasugrel, or ticagrelor could be added, as he does not have a

contraindication to any of these drugs. Ticagrelor may be preferred as long as cost is

not a concern for the patient.

After PCI with coronary stent deployment with either a drug-eluting or bare metal

stent, clopidogrel 75 mg, prasugrel

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p. 256

5 to 10 mg, or ticagrelor 90 mg twice daily should be administered for at least 12

months. It is important to highlight that clopidogrel and ticagrelor should be

discontinued for 5 days and prasugrel for 7 days, prior to surgery.

As a rapid onset of action is needed, J.W. should receive a loading dose of 600 mg

of clopidogrel as soon as possible, followed by 75 mg daily for at least 12 months. If

prasugrel is chosen, a loading dose of 60 mg would be given followed by 10 mg

daily as long as the patient is >60 kg. For ticagrelor, a loading dose of 180 mg is

recommended following by 90 mg twice daily. Aspirin 81 mg daily should be

continued indefinitely.

CASE 13-2, QUESTION 5: Should a GP IIb/IIIa inhibitor be added? If so, which one?

In patients with NSTE-ACS, the GP IIb/IIIa inhibitors are of benefit for patients

considered high risk, those undergoing PCI, or both.

1 Analysis of GP IIb/IIIa studies

suggest that those patients who obtain the greatest advantage from these agents are

those who have elevated troponins, diabetes, ST segment changes, or a TIMI risk

score of 4 or higher at presentation. The guidelines recommend that for patients with

NSTE-ACS who will be treated initially according to an invasive strategy, either a

GP IIb/IIIa inhibitor or a P2Y12

inhibitor (clopidogrel or ticareglor), should be

added to aspirin and anticoagulant therapy before diagnostic angiography is

performed.

1 When used to treat patients medically, the GP IIb/IIIa inhibitors tirofiban

or eptifibatide are generally given for 18 to 72 hours. Abciximab should be used only

with PCI. (Table 13-6).

1

The GUSTO-IV-ACS trial enrolled patients with NSTE-ACS in whom early (<48

hours) revascularization was not intended. All patients received aspirin and either

UFH or LMWH.

81 They were randomized to placebo, abciximab bolus and 24-hour

infusion, or abciximab bolus and 48-hour infusion. At 30 days, death or MI occurred

in 8.0% of patients receiving placebo, 8.2% of patients receiving 24-hour abciximab,

and 9.1% of patients receiving 48-hour abciximab (no significant difference). At 48

hours, death occurred in 0.3%, 0.7%, and 0.9% of patients in these groups,

respectively (placebo vs. abciximab at 48 hours; p = 0.008). Based on these findings

and those of other studies, abciximab is indicated only if angiography will not be

appreciably delayed and PCI is likely to be performed; otherwise, IV eptifibatide or

tirofiban is preferred (Fig. 13-6).

The guidelines recommend that in the setting of dual antiplatelet therapy used with

UFH, the adjunctive use of a GP IIb/IIIa inhibitor administered at the time of PCI

cannot be recommended as routine therapy. However, a GP IIb/IIIa inhibitor may be

beneficial in those with a large thrombus burden or who have not received adequate

P2Y12 antagonist loading.

1

J.W. has a TIMI risk score of 4; therefore, the addition of eptifibatide or tirofiban

is a reasonable choice if a large thrombus burden is demonstrated on angiography.

Administration prior to PCI (“upstream”) is not indicated unless the administration of

a P2Y12 antagonist is delayed until time of PCI. Platelets and signs and symptoms of

bleeding should be monitored closely.

Because J.W. is not at high risk for bleeding, dual antiplatelet therapy in addition

to UFH should be adequate therapy. If a large thrombus burden is demonstrated on

angiography, a GP IIa/IIIb could be initiated during PCI.

If J.W. had not received an oral P2Y12

inhibitor or a GP IIb/IIIa inhibitor,

consideration could be given to administering IV cangrelor, a direct-acting P2Y12

platelet inhibitor, prior to PCI. Based on the results of the CHAMPION PHOENIX

trial, cangrelor could be administered as a 30 mcg/kg bolus followed by a 4

mcg/kg/minute IV infusion for at least 2 hours or for the duration of the PCI.

29 After

discontinuation of the infusion, an oral P2Y12

inhibitor should be administered

(ticagrelor 180 mg load during or upon immediate discontinuation of infusion;

prasugrel 60 mg or clopidogrel 600 mg upon immediate discontinuation of infusion)

followed by aspirin 81 mg daily along with a maintenance dose of the P2Y12

inhibitor. If clopidogrel or prasugrel are administered during the infusion, they will

have no antiplatelet effect until the next dose is administered.

CASE 13-2, QUESTION 6: What if an ischemia-driven strategy was decided for J.W. instead, would his

antithrombotic therapy change?

Table 13-6

Dosing of Glycoprotein IIb/IIIa in Acute Coronary Syndromes

1,5

Medication Dosing for STEMI PCI

Dose for NSTE-ACS

With or Without PCI Comments

Abciximab 0.25 mg/kg IV bolus Not recommended

followed by 0.125

mcg/kg/minute infusion

(max of 10 mcg/minute),

continue for 12 hours at

the discretion of the

physician

Eptifibatide 180 mcg/kg IV bolus, then

begin 2 mcg/kg/minute

infusion followed by

second IV bolus of 180

mcg/kg 10 minutes after

first bolus, continue

infusion for 12–18 hours

after PCI at the discretion

of the physician

180 mcg/kg IV bolus, then

begin 2 mcg/kg/minute

infusion, continue infusion

for 12–18 hours

Repeat bolus dose after 10

minutes for PCI

Reduce infusion by 50% in

patients with CrCl <50

mL/minute; not studied in

patients with SCr >4.0

mg/dL; avoid in

hemodialysis

Tirofiban 25 mcg/kg IV bolus

followed by an infusion of

0.15 mcg/kg/minute,

continue up to 18 hours at

the discretion of the

physician

25 mcg/kg IV bolus within

5 minutes followed by an

infusion of 0.15

mcg/kg/minute (or 0.075

mcg/kg/minute for patients

with CrCl ≤60

mL/minute), for up to 18

hours.

Reduce infusion by 50% in

patients with CrCl < 30

mL/minute

CrCl, creatinine clearance; IV, intravenous; NSTE-ACS, non–ST segment elevation acute coronary syndrome;

PCI, percutaneous coronary intervention; SCr, serum creatinine; STEMI, ST segment elevation myocardial

infarction.

p. 256

p. 257

Management Strategy

ISCHEMIA-GUIDED STRATEGY

An ischemia-guided strategy avoids early invasive procedures, instead relying on the

patient’s symptoms to direct the need for intervention. Similarly, J.W. would be

optimized on anti-ischemic and antithrombotic regimens. At this time, prasugrel and

bivalirudin are only indicated in patients undergoing PCI. Additionally, the bleeding

risk of GP IIb/IIIa inhibitors outweighs the benefit in this approach and therefore

these medications should only be used if PCI is pursued. If during his hospitalization,

the patient were to experience any recurrent ischemia, refractory angina despite

medical therapy, or high-risk features (e.g., arrhythmias, signs or symptoms of HF,

hemodynamic instability, elevated cardiac enzymes), an invasive approach would be

pursued.

1

LONG-TERM THERAPY

Angiotensin-Converting Enzyme Inhibitors,

Angiotensin Receptor Blockers, and Direct Renin

Inhibitors

CASE 13-3

QUESTION 1: J.S. is a 68-year-old man who presents with a STEMI along with signs and symptoms of HF.

His past medical history includes hypertension treated with hydrochlorothiazide 25 mg daily and diabetes for

which he takes metformin 500 mg twice daily. He has smoked a pack of cigarettes per day for the past 40

years. On admission, his BP was 145/86 mm Hg, and his heart rate was 90 beats/minute. His weight is 91 kg

with a height of 5’9” and a body mass index (BMI) of 29.5 kg/m

2

. Laboratory values include the following:

Na, 139 mEq/L

K, 4.2 mEq/L

Cl, 100 mEq/L

CO2

, 20 mEq/L

BUN, 15 mg/dL

SCr, 1.3 mg/dL

Glucose, 130 mg/dL

Hemoglobin A1c

, 6.9%

Mg, 2 mEq/L

CK-MB fraction, 35% (normal, 0%–5%)

Troponin I-Ultra, 10 ng/mL (normal, <0.02 ng/mL)

He is administered aspirin 325 mg, prasugrel 60 mg, IV NTG infusion, continuous infusion of UFH, and

intranasal oxygen. J.S. is immediately sent to the catheterization laboratory in which he receives a drug-eluting

stent in his left anterior descending artery. After stabilization of his HF symptoms, J.S. is started on oral

metoprolol tartrate 25 mg every 6 hours. An echocardiogram is performed before discharge and shows an

LVEF of 35% along with the appearance of a thrombus in the LV.

Is an ACE inhibitor appropriate for J.S.? When should an ARB be considered?

After an AMI, the heart undergoes processes that initially compensate for the loss

of contractile function but may increase the long-term risk for development of HF.

This is referred to as remodeling of the ventricle (see Chapter 14, Heart Failure).

The increase in the number of survivors of AMI has led to an increase in the number

of HF patients. A number of clinical trials with the use of ACE inhibitors have

demonstrated reductions in HF symptoms and mortality after MI.

5

For patients with ACS, oral ACE inhibitor therapy should be started within the

first 24 hours of presentation for those with an LVEF of 40% or less (even if

asymptomatic) or clinical evidence of HF. Additionally, ACE inhibitors should also

be considered for patients with concomitant hypertension, diabetes, and/or chronic

kidney disease.

5 The use of IV ACE inhibitor therapy is not recommended. Because

of its short half-life, captopril could be given on postinfarction day 2 or 3, beginning

with a test dose of 6.25 mg and then titrated as tolerated. Once it is established that

the patient can tolerate an ACE inhibitor, he or she can be switched to a once daily

agent such as lisinopril to simplify the regimen. The BP should be monitored closely,

with systolic BP maintained greater than 90 mm Hg. Renal function and serum

potassium levels should be monitored closely during the first few months of therapy.

Because J.S. presents with clinical symptoms of HF, he is a candidate for an ACE

inhibitor. Additionally, J.S. has an EF of less than 40%, hypertension, and diabetes,

therefore the ACE inhibitor should be continued indefinitely (Table 13-2).

If the patient cannot tolerate an ACE inhibitor because of cough, an ARB may be

an alternative. In the Optimal Therapy in Myocardial Infarction with the Angiotensin

II Antagonist Losartan (OPTIMAAL) trial and Valsartan in Acute Myocardial

Infarction Trial (VALIANT), losartan and valsartan demonstrated similar reductions

in all-cause mortality compared with captopril.

82,83 Dual therapy of ACE inhibitors

with ARBs offers no additional benefits but increases side effects.

Aldosterone Antagonists

CASE 13-3, QUESTION 2: Should J.S. receive an aldosterone antagonist?

Like angiotensin II, aldosterone plays an important role in LV remodeling.

Inhibiting aldosterone directly in addition to ACE inhibitor therapy was first

evaluated in HF patients in the Randomized Aldactone Evaluation Study (RALES)

(see Chapter 14, Heart Failure). Another aldosterone antagonist, eplerenone, is a

selective inhibitor of the mineralocorticoid receptor with fewer sexual side effects.

In the Eplerenone Post Acute Myocardial Infarction Heart Failure Efficacy and

Survival Study (EPHESUS), patients with AMI and EF less than 40% receiving

optimal medical therapy were randomized to eplerenone or placebo.

35 Significant

reductions in mortality (15%), sudden death (13%), and cardiovascular death or

hospitalization (21%) were seen with eplerenone compared to placebo.

The ACC/AHA guidelines recommend an aldosterone antagonist in patients with

NSTE-ACS or STEMI who are already receiving therapeutic doses of an ACE

inhibitor, have an EF less than 40%, and have either symptomatic HF or diabetes.

1,5

Potential contraindications to the use of an aldosterone antagonist in this setting

include significant renal dysfunction (creatinine > 2.5 mg/dL in men, >2.0 mg/dL in

women, or creatinine clearance < 30 mL/minute) or hyperkalemia (potassium > 5

mEq/L).

Because J.S. has symptomatic HF with an EF less than 40% and diabetes, he is a

candidate for an aldosterone antagonist. Serum potassium and renal function need to

be checked in 2 to 3 days and 1 week after therapy initiation, then every month for the

first 3 months. ACE inhibitor and potassium supplement doses may need to be

adjusted.

84

β-Blockers

CASE 13-3, QUESTION 3: Should J.S. receive a β-blocker on discharge?

p. 257

p. 258

The ACC/AHA guidelines recommend continued β-blocker therapy at discharge

for all patients after ACS.

1,5 The benefits of β-blockers in reducing reinfarction and

mortality outweigh the risk, even in patients with asthma, depression, insulindependent diabetes, severe peripheral vascular disease, first-degree heart block, and

moderate LV dysfunction. Atenolol, propranolol, carvedilol, metoprolol tartrate, and

metoprolol succinate are generic, making them cost-effective. Metoprolol succinate,

carvedilol, and bisoprolol are considered first-line choices in patients with HF,

whereas atenolol, metoprolol tartrate, or metoprolol succinate should be considered

in patients with stable asthma or bronchospastic pulmonary disease. Being

discharged on a β-blocker is a quality performance measure.

85 However, debate

exists surrounding the duration of use, especially in low-risk patients without

compelling indications.

86–89 Data suggest that the benefits from β-blockers emerge

early following an AMI and are maintained out to 1 year. Although the exact duration

of benefit is unknown, high-risk patients (e.g., GRACE score ≥ 121 and diuretic use)

are likely to continue to derive benefit for up to 3 years. The 2011 AHA/ACCF

secondary prevention guidelines recommend a 3-year treatment course for patients

with normal LV function, with an option to continue indefinitely as long as the

medication is well tolerated. Because J.S. has a low EF, he should be transitioned

from oral metoprolol tartrate to metoprolol succinate, carvedilol, or bisoprolol,

which should be continued indefinitely.

Lipid-Lowering Agents

CASE 13-3, QUESTION 4: Should J.S. be started on a lipid-lowering agent? If so, which one? When should

it be initiated?

A complete fasting lipid profile would be helpful and should be completed within

24 hours of presenting with an AMI.

1,5 This is often overlooked or not done because

the patient is not fasting. Most patients will require a low-cholesterol, low-saturated

fat diet in addition to lipid-lowering therapy. The ACC/AHA STEMI and NSTEACS guidelines recommend that a high-intensity statin therapy be initiated or

continued in all patients with ACS unless contraindications are present.

1,5 This would

consist of atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg daily.

34 When

triglycerides are 500 mg/dL or more, drug therapy with niacin or a fibrate is

beneficial.

89

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering

(MIRACL) trial evaluated NSTE-ACS patients receiving atorvastatin 80 mg/day or

placebo within 24 to 96 hours of hospitalization. A significantly lower rate of death

and nonfatal major cardiac events at 4 months of follow-up was seen in patients

receiving atorvastatin.

90

In the Pravastatin or Atorvastatin Evaluation and Infection

Therapy (PROVE-IT)-TIMI 22 trial, patients with ACS who received atorvastatin 80

mg/day for 10 days exhibited a significantly lower risk of death, MI, UA

hospitalization, stroke, and revascularization when compared with pravastatin 40

mg/day.

90 The A to Z trial showed a favorable trend toward major cardiovascular

event reduction in AMI patients receiving an intensive simvastatin regimen (40

mg/day for 1 month followed by 80 mg/day thereafter) when initiated within 12 hours

of stabilization compared to a less intensive regimen (placebo for 4 months followed

by simvastatin 20 mg/day).

91 However, based on clinical trials, observational

studies, adverse event reports, and prescription use data, simvastatin 80 mg may be

associated with increased muscle injury (refer to Chapter 8, Dyslipidemias,

Atherosclerosis, and Coronary Heart Disease).

34

In the case of J.S., he should receive a high-intensity statin within 24 hours of his

hospitalization and be discharged on a statin regardless of LDL cholesterol. This is a

quality core performance measure.

85 Drug interactions, patient tolerability, and

affordability should be considered. Currently, the LDL goal for patients with ACS

remains controversial. The ACC/AHA STEMI and NSTE-ACS guidelines do not

recommend a specific goal LDL. However, the National Lipid Association does

recommend a goal LDLless than 100 mg/dLin patients with ACS.