Guideline-Based Management of a Patient With STEMI Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI

Patient History

KD, a 73-year-old woman, presented to the emergency department with burning pain in her chest. She arrived by

ambulance at 12:37 AM after calling 911 at 12:14 AM. While the ambulance was en route to the hospital, the crew gave her

sublingual nitroglycerin and had her chew an aspirin tablet. In her interview with the triage nurse, KD stated that the pain

woke her from sleep at about 11 PM. She tried some of her husband's over-the-counter antacid tablets but the pain

worsened and she decided to call 911. She has no history of heart disease or heartburn. She was placed on a cardiac

monitor, which found a heart rate of 110 beats/min.

What is the appropriate next action for this patient?

Take a detailed history and perform a physical examination

Take blood samples for troponin testing

Perform 12-lead electrocardiography (ECG)

Take a chest x-ray

Possible symptoms of STEMI include chest discomfort or pain, which may radiate to other locations; shortness of breath;

diaphoresis; nausea; light-headedness; and anginal equivalents.[1]

Chest discomfort or pain is particularly suggestive of STEMI, and the current American Heart Association/American College

of Cardiology (AHA/ACC) guidelines state that a 12-lead ECG should be obtained and examined within 10 minutes of arrival

at the emergency department for all patients who present with chest discomfort, anginal equivalents, or other symptoms

suggestive of STEMI. The 12-lead ECG is a core element in the diagnostic pathway for STEMI and is critical to early

diagnosis and identification of patients who require early effective therapy.[1] Medical history, blood tests, and x-rays are an

important part of the workup and are secondary to ECG for accurate and initial diagnosis.

By what percentage does a 30-minute delay in reperfusion increase 1-year mortality in patients with

STEMI?

1%

7.5%

15%

30%

Rapid reperfusion is a critical goal in treating patients who have had STEMI. Regardless of the method, the time between

symptom onset and reperfusion is a key factor in determining outcome. For instance, a study by De Luca and colleagues[2] in

patients who underwent primary percutaneous coronary intervention (PCI; n = 1791) found that a 30-minute delay in

reperfusion causes a 7.5% relative increase in 1-year mortality. Similarly, a study by McNamara and colleagues[3] using data

from the National Registry of Myocardial Infarction (NRMI) found that mortality increased with increasing door-to-balloon

time in 29,222 patients with STEMI. The mortality rate was 3.0%, 4.2%, 5.7%, and 7.4% for door-to-balloon times of ≤ 90

min, 91-120 min, 121-150 min, and > 150 min, respectively; P for trend: < .01).

Because of the close relationship between reperfusion time and outcomes, it is important to minimize the delay between

symptom onset and reperfusion. Much of this delay (ie, door-to-needle time for fibrinolytic therapy or door-to-balloon time for

PCI), occurs at the hospital and can be minimized by optimizing the hospital's protocols. However, the time between

symptom onset and arrival at the emergency department is also important. Several approaches have been used to try to

minimize this delay.

Patient education is a critical issue. Many patients do not recognize the symptoms of STEMI, particularly atypical symptoms.

Those who do not recognize their symptoms as indicating a possible heart attack are unlikely to call 911 right away, as

occurred in this case, or even at all. Patient education programs are ongoing at the national level. These include the

National Heart, Lung and Blood Institute's "Act in Time to Heart Attack Signs" program and the AHA's "Mission Lifeline."

Both programs are intended to teach patients to recognize heart attack signs, go to the hospital earlier, and be transported

via ambulance.[4,5]

Appropriately trained and equipped emergency response systems can also decrease the time to treatment by acquiring a

prehospital ECG or providing prehospital fibrinolysis. According to the STEMI guidelines put forth by the ACC and the AHA,

prehospital ECGs are an effective but underused strategy for improving care of patients with STEMI.[6] Unfortunately, the

barriers to implementation of prehospital ECG systems are substantial, and implementation is far from universal in the

United States.[7]

Prehospital fibrinolysis also appears to be effective. A meta-analysis found that prehospital fibrinolysis was associated with

significantly less mortality than in-hospital fibrinolysis.[1] In the CAPTIM (Comparison of Angioplasty and Prehospital

Thrombolysis in Acute Myocardial Infarction) trial, prehospital fibrinolysis was not inferior to PCI and appeared to be superior

to PCI for patients treated within 2 hours of symptom onset.[1,8,9]

Which statement correctly describes patients with STEMI who present with atypical or typical

symptoms?

Approximately 33% of STEMI patients present with atypical symptoms (ie, no chest pain or

discomfort)

Approximately 8% of STEMI patients present with atypical symptoms (ie, no chest pain or

discomfort)

Approximately 1% of STEMI patients present with atypical symptoms (ie, no chest pain or

discomfort)

Approximately 50% of STEMI patients present with typical symptoms (ie, no chest pain or

discomfort)

Although the symptoms of STEMI usually include chest pain, a considerable number of patients present without it. In a study

based on the GRACE (Global Registry of Acute Coronary Events) registry reported by Brieger and colleagues [10] in 2004,

atypical presentations occurred in 541 of 6926 patients (7.8%) ultimately diagnosed with STEMI. In the entire study sample,

which consisted of 20,881 patients with any acute coronary syndromes, 1763 patients presented without chest pain. Of

these, 23.8% were diagnosed incorrectly on presentation. In contrast, only 2.4% of patients who presented with chest pain

were diagnosed incorrectly.

Patients with STEMI who presented with atypical symptoms were less likely to receive fibrinolysis, PCI, aspirin, or beta-

blockers than those with typical symptoms (Table 1). This difference in care is reflected in mortality rates, which were almost

3-fold higher for patients with atypical symptoms than for those with typical symptoms.[10]

Table 1. Hospital Management and Outcomes of STEMI: Percentage of Patients With STEMI Who Received Each

Specified Therapy or Had Each Outcome, by Presence or Absence of Chest Pain

Variable Patients, %

P value No Chest Pain (n = 541) Chest Pain (n = 6385)

Intervention

Fibrinolysis 25.6 45.6 <.001

Primary PCI 11.0 21.0 <.001

Beta-blockers (within first 24 hours) 54.5 68.5 <.001

Aspirin (within first 24 hours) 86.3 92.8 <.001

Outcome

In-hospital mortality 18.7 6.3 <.001

PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction

Data from Brieger, et al.[10]

Delayed diagnosis and treatment are associated with adverse outcomes; as a result, it is critical to recognize the possibility

of STEMI in patients who present with atypical symptoms. Dominant presenting symptoms among patients who presented

without chest pain and were ultimately diagnosed with an acute coronary syndrome in the GRACE registry study include

dyspnea (49.3%), diaphoresis (26.2%), nausea and vomiting (24.3%), and syncope (19.1%).[10] Atypical presentations are

more common among older patients and patients with diabetes.[1,4] Atypical presentations may also be more common in

women than men. A heightened index of suspicion for STEMI is warranted for women, although evidence of higher

prevalence of atypical symptoms in this group is not entirely conclusive.[1]

Case Presentation, Continued

Nine minutes after KD's initial presentation, a 12-lead ECG showed 2- to 3-mm ST elevation in leads V3, V4, V5, and V6.

The hospital has a 24-hour PCI facility, which is usually ready within 40 minutes of activation.

What is the appropriate next action for this patient?

Initiate fibrinolytic therapy

Take a history and perform a physical examination

Initiate laboratory tests to confirm a diagnosis of STEMI

Activate the PCI facility

An ECG showing ST-segment elevation is sufficient to identify patients who can benefit from reperfusion therapy. Several

laboratory tests and procedures in addition to the ECG are valuable for guiding therapeutic decisions. However, once ST-

segment elevation is identified, cardiac biomarker testing and other laboratory examinations should not delay

implementation of reperfusion therapy.[1]

The core goal of reperfusion is to minimize the total ischemic time by quickly providing reperfusion therapy.[1] The target time

is 90 minutes from first medical contact to balloon insertion for PCI or 30 minutes for fibrinolytics. PCI is preferred if the 90-

minute target is achievable.[6] Several situations also favor PCI over fibrinolytics[1]:

Cardiogenic shock;

Killip class III or IV;

Contraindications to fibrinolytics;

Presentation at more than 3 hours after symptom onset; and

STEMI diagnosis is uncertain.

In general, PCI is contraindicated only if it cannot be provided within the 90-minute target time. This could occur if, for

instance, PCI cannot be provided promptly at the hospital where the patient initially presented and transport to a PCI-

capable facility would take too long, or if vascular access is difficult.

In the case of KD, the anticipated first-contact-to-balloon time is 82 minutes: 23 minutes from the 911 call to arrival at the

emergency department, 9 minutes for diagnosis of the ECG, and 50 minutes to activate the PCI facility. This is well within

the 90-minute target.

Which conditions are considered absolute contraindications to fibrinolytic therapy?

History of intracranial hemorrhage (ICH) or recent internal bleeding

Pregnancy

History of hypertension or diabetes controlled by medication

History of recent acute cardiac syndrome

Although PCI is preferred over fibrinolytic therapy when PCI can be performed promptly, this preference should not obscure

the importance of time to reperfusion or the value of fibrinolytics in providing rapid reperfusion when PCI is not available

within 90 minutes. Hospitals that cannot provide prompt PCI should be able to initiate fibrinolytic therapy within 30 minutes of

presentation and should have written protocols in place for transferring patients to PCI-capable facilities when fibrinolytics

are contraindicated.[1,6]

Bleeding, especially ICH, is the primary risk of fibrinolytic therapy. Percutaneous coronary intervention should be

increasingly favored over fibrinolytics as the patient's risk for bleeding increases, and contraindications to fibrinolytics center

on patients with an increased risk for bleeding (Table 2).[1] Patients should be evaluated for bleeding risk factors as part of

their initial history and physical examination.[1]

Table 2. Contraindications for Fibrinolytic Therapy in Patients With STEMI*

Absolute Contraindications

Any prior intracranial hemorrhage

Known structural cerebrovascular lesion (eg, arteriovenous malformation)

Known malignant intracranial neoplasm (primary or metastatic)

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

Suspected aortic dissection

Active bleeding or bleeding diathesis (excluding menses)

Significant closed-head or facial trauma within 3 months

Relative Contraindications

History of chronic, severe, poorly controlled hypertension

Severe uncontrolled hypertension on presentation (systolic blood pressure > 180 mm Hg; diastolic > 110 mm Hg)†

History of prior ischemic stroke > 3 months, dementia, or known intracranial pathology not covered in contraindications

Traumatic or prolonged (> 10 minutes) cardiopulmonary resuscitation or major surgery (within 3 weeks)

Recent (within 2-4 weeks) internal bleeding

Noncompressible vascular punctures

Prior exposure (> 5 days ago) or prior allergic reaction to streptokinase or anistreplase

Pregnancy

Active peptic ulcer

Current use of anticoagulants: the higher the International Normalized Ratio, the higher the risk for bleeding

Data from Antman, et al.[1]

Which biomarker should be assessed after activation of the PCI facility?

Cardiac troponins

Creatine kinase (CK)

CK-MB

Myoglobin

Cardiac troponins are highly specific and sensitive for myocardial necrosis and are the preferred diagnostic marker for MI.

However, abnormal troponins may not appear in the blood for 3-6 hours after symptom onset. This is too late to be reliable

in making a timely diagnosis of STEMI, and patients with STEMI may present without elevated troponin levels. Because they

remain elevated for several days after STEMI, troponins are not reliable for detection of reinfarction.[1]

CK can be produced by injured skeletal muscle (eg, after an intramuscular injection) as well as by injured myocardium and is

therefore less specific than troponins. CK-MB is more specific than CK and responds faster than the troponins. Figure 1

shows changes in serum levels of cardiac troponin and CK-MB with and without reperfusion. It is the preferred biomarker for

monitoring reperfusion and detecting reinfarction. However, elevated CK-MB can result from cardiac stressors other than MI.

Myoglobins are nonspecific but respond quickly, sometimes within 2 hours of the infarction.[1,11]

Figure 1. Changes in levels of cardiac biomarkers with and without reperfusion.

Adapted from Antman, et al.[1]

Serum cardiac biomarkers are valuable diagnostic and prognostic tools in the management of patients with suspected MI.[1]

However, their utility for initial diagnosis of STEMI is limited because of the delay between the onset of STEMI and the

appearance of elevated serum biomarker levels, the limited specificity of some markers for cardiac damage, and the time

required to obtain laboratory values. Thus, 12-lead ECG is the primary tool for the initial diagnosis of STEMI, and cardiac

biomarkers are used primarily for confirmation, detection of small infarctions, and estimation of the size of the infarction. [1]

Reperfusion should not be delayed pending laboratory results in a patient with STEMI diagnosed by ECG.[1]

Bedside biomarker tests can provide qualitative results within a few minutes and are fast enough to be useful in confirming a

diagnosis of MI if elevated troponins are present, particularly if the ECG is ambiguous. However, bedside tests are less

sensitive and precise than quantitative laboratory assays and should be confirmed by a laboratory assay.[1]

Other biomarkers and laboratory evaluations are useful in managing patients with STEMI. Table 3 lists the laboratory

evaluations recommended in the ACC/AHA STEMI guidelines.

Table 3. Laboratory Evaluations Recommended for the Management of STEMI in the ACC/AHA STEMI Guidelines

Serum biomarkers for cardiac damage (do not wait for results before implementing reperfusion strategy)

Complete blood count, including platelet count

International Normalized Ratio

aPTT

Electrolytes and magnesium

Blood urea nitrogen

Creatinine

Glucose

Serum lipids

aPTT = activated partial thromboplastin time; STEMI = ST-segment elevation myocardial infarction

Data from Antman, et al.[1]

Case Presentation, Continued

The emergency department physician activated the PCI facility. The interventional cardiologist on call confirmed that the

facility would be ready within 40-50 minutes. While the PCI facility personnel were in transit and setting up the facility, the

emergency team continued their evaluation. During this evaluation, KD reported mild nausea and dyspnea in addition to

chest pain. She had no radiated pain. Her medical history included diagnoses of hypertension and hypercholesterolemia at

least a decade ago. She has been treated with hydrochlorothiazide 25 mg/day and simvastatin 20 mg/day since then.

Physical examination found that KD is mildly obese, with a body mass index of 32 kg/m2. Her vital signs were heart rate 110

beats/min, blood pressure 150/70 mm Hg, and respiratory rate 12 breaths/min. She was afebrile, and her lungs were clear.

Heart rhythm was regular with normal S1 and S2, positive S4, and intact peripheral pulses. No peripheral edema was

apparent. A bedside troponin test was positive. Chest x-ray found no evidence of aortic dissection.

A blood sample was drawn for CK-MB and routine laboratory analyses, including creatinine, complete blood count, blood

urea nitrogen, electrolytes, baseline lipids, prothrombin time, and partial thromboplastin time, were done.

The PCI facility was ready 47 minutes after the call. The procedure went smoothly; reperfusion and stent placement were

successful. The total contact-to-balloon time was 70 minutes.

On the basis of clinical evidence, which statement correctly describes anticoagulant therapy in PCI

patients?

Anticoagulant therapy is not appropriate for a patient like KD

A combination of 2 or more anticoagulation agents is appropriate

Patients taking enoxaparin (vs unfractionated heparin [UFH]) are more likely to reach

anticoagulation levels

Similar results can be expected when fondaparinux is used alone or with heparin

Montalescot and colleagues[12] compared enoxaparin with UFH in 3528 patients who underwent elective PCI. Non-CAGB-

related bleeding rates were 8.5% with UFH, 5.9% with enoxaparin 0.5 mg/kg, and 6.5% with enoxaparin 0.75 mg/kg. The

difference was highly significant (P = .01) for enoxaparin 0.5 mg/kg vs UFH and almost significant (P=0.51) for enoxaparin

0.75 mg/kg vs UFH. With both enoxaparin doses, rates of major bleeding were significantly lower than with UFH, and

patients were significantly more likely to reach target anticoagulation levels.

The 2008 update of the ACC/AHA guidelines includes a discussion of UFH, enoxaparin (low-molecular-weight heparin), and

fondaparinux as anticoagulant therapies for patients with STEMI.[6] Data on use of any of these agents in patients

undergoing primary PCI are limited. The guidelines state that patients undergoing primary PCI should receive UFH in a

weight-adjusted bolus of 70-100 U/kg.[1]

The core analysis of EXTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction

Treatment [ExTRACT]- Thrombolysis in Myocardial Infarction [TIMI]) compared UFH with enoxaparin in 20,479 STEMI

patients.[13] Of these, 4676 patients underwent PCI within 30 days of the initial event, and these patients were evaluated in a

subgroup analysis. In the analysis, patients who received enoxaparin were less likely to require PCI than those who received

UFH (22.8% vs 24.2%, P = .0027). Major events occurred in 11.5% of patients receiving enoxaparin vs 14.8% of patients

receiving UFH (Figure 2) (relative risk, 0.78; 95% confidence interval [CI], 0.67-0.90; P < .001). The difference emerged

before PCI and persisted for up to 30 days.[14]

Figure 2. Rates of death or MI among patients undergoing PCI in EXTRACT-TIMI 25.

Adapted from Gibson, et al.[14]

For fondaparinux, the OASIS-6 trial compared fondaparinux vs usual care (placebo or UFH depending on whether the

investigator felt that UFH was indicated) in 12,092 patients with STEMI. Of these, 3788 patients underwent primary PCI, and

rates of death and MI were similar between controls and patients receiving fondaparinux. However, catheter thrombosis and

coronary complications were more common among patients receiving fondaparinux.[15] Thus, if fondaparinux is used, it

should be used with an agent having anti-IIa activity for PCI to minimize the risk for catheter thrombosis.[6]

Stone and coworkers[16] reported on a comparison of the direct thrombin inhibitor bivalirudin vs heparin plus glycoprotein

IIb/IIIa inhibitors in STEMI patients from the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial

Infarction (HORIZONS-AMI) study. A total of 3602 patients with STEMI presented within 12 hours after the onset of

symptoms and were scheduled for primary PCI. These patients were treated with either bivalirudin vs heparin plus

glycoprotein IIb/IIIa inhibitors (either abciximab or eptifibatide). Treatment with bivalirudin resulted in a reduced rate of net

adverse clinical events at 30 days (9.2% vs 12.1%; relative risk, 0.76; 95% CI, 0.63-0.92; P = .005) due to a lower rate of

major bleeding (4.9% vs 8.3%; relative risk, 0.60; 95% CI, 0.46-0.77; P < .001).

Which antiplatelet therapy would be appropriate for KD?

Aspirin alone

Clopidogrel

Ticlopidine

Aspirin and clopidogrel in combination

Antiplatelet therapy is not appropriate

The updated ACC/AHA guidelines recommend both aspirin and clopidogrel for all patients with STEMI regardless of the

reperfusion strategy used.[6] Patients with a suspected STEMI should receive aspirin as early as possible at an initial dose of

162-325 mg, and therapy should continue indefinitely at a maintenance dose of 75-162 mg. Aspirin is contraindicated only

for patients with a true aspirin allergy.[1] The benefits of aspirin in the setting of STEMI have been known since at least 1988,

when the ISIS-2 (Second International Study of Infarction Survival) study found that aspirin significantly reduced nonfatal

reinfarction (1.0% vs 2.0%).[17]

Patients with STEMI should receive clopidogrel 75 mg/day in addition to aspirin for at least 14 days; longer durations are

recommended for patients who receive a stent. The recommended duration depends on the type of stent: For a bare-metal

stent, clopidogrel should continue for at least 1 month and ideally 12 months; patients who receive a drug-eluting stent

should receive clopidogrel for at least 12 months. The duration of therapy should be reduced for patients at high risk for

bleeding.[8]

Several studies, including PCI-CURE (The PCI-Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events),[18]

PCI-CLARITY (The PCI-Clopidogrel as Adjunctive Reperfusion Therapy),[19] and CREDO (Clopidogrel for the Reduction of

Events During Observation),[20] have demonstrated that clopidogrel in combination with aspirin is more effective than aspirin

alone.

The PCI-CURE study, reported by Mehta and colleagues[18] in 2001, compared clopidogrel plus aspirin to placebo plus

aspirin in 2658 patients with non-ST-elevation MI or unstable angina who had PCI a median of 10 days after symptom onset.

Patients who received clopidogrel were significantly less likely to experience MI or cardiovascular death than those who

received placebo, with rates of MI or death at 8.8% for clopidogrel vs 12.6% for placebo (relative risk 0.69; 95% CI, 0.54-

0.87; P = .002).

PCI-CLARITY, reported by Sabatine and colleagues[19] in 2005, was a subgroup analysis of CLARITY-TIMI 28. The parent

trial compared clopidogrel plus aspirin with placebo plus aspirin in 3491 STEMI patients who were treated with fibrinolysis.

Approximately half of these patients (1863, 53.4%) went on to undergo PCI during the index hospitalization, at a median of 3

days after the initiation of the study drug. Among these patients, pretreatment with clopidogrel significantly reduced rates of

the combined endpoints of cardiovascular death, recurrent MI, or stroke within 30 days for the overall sample, regardless of

the patient's age, sex, diabetes status, or infarct location. Table 4 summarizes the post-PCI outcomes.

Table 4. Summary of 30-Day Outcomes After PCI in PCI-CLARITY

Outcome Patients, n (%)

Adjusted Odds Ratio (95% CI) P Value Clopidogrel (n = 933) Placebo (n = 930)

Cardiovascular death, MI, or stroke 34 (3.6) 58 (6.2) 0.54 (0.35-0.85) .008

Cardiovascular death or MI 31 (3.3) 50 (5.4) 0.58 (0.36-0.94) .03

Cardiovascular death 13 (1.4) 24 (2.6) 0.49 (0.24-1.03) NR

MI 18 (1.9) 29 (3.1) 0.60 (0.33-1.11) NR

Stroke 4 (0.4) 11 (1.2) 0.35 (0.11-1.11) NR

MI = myocardial infarction; NR = not reported; PCI = percutaneous coronary intervention

Data from Sabatine, et al.[19]

CREDO compared early, sustained clopidogrel therapy (a 300-mg loading dose followed by 75 mg/day for 1 year) with

standard clopidogrel therapy (75 mg/day for 1 month) in 2116 patients who had evidence of coronary ischemia, were

undergoing elective PCI, or had a high likelihood of requiring PCI.[20] The results were analyzed at 28 days to assess the

loading dose and at 1 year to assess sustained therapy. The loading dose did not significantly reduce 28-day rates of the

combined endpoint (6.8% with loading dose vs 8.3% without; relative risk reduction, 18.5%; 95% CI, -14.2 to 41.8%; P =

.23). Patients who received early, sustained therapy had significantly lower risk for the combined endpoint (death, MI, or

stroke) at 1 year than those who received conventional therapy, with rates of 8.5% and 11.5% in the sustained- and

conventional-therapy groups, respectively (relative risk reduction, 26.9%; 95% CI, 3.9-44.4%; P = .02). Figure 3 shows

results for the combined endpoint at 1 year.

Figure 3. Occurrence of death, MI, stroke, for clopidogrel 75 mg vs placebo in CREDO.

Adapted from Steinhubl, et al[20]

Clopidogrel was also evaluated as a preventive therapy among 15,603 patients with multiple risk factors for cardiovascular

disease or clinically evident stable disease. Clopidogrel did not provide a significant benefit in the overall sample or in the

subgroup of patients with risk factors but no documented vascular disease, but it did provide a marginally significant

reduction in the risk for cardiovascular death, MI, or stroke among patients with documented cardiovascular disease.

However, clopidogrel increased the risk for bleeding.[21] Table 5 summarizes the results.

Table 5. Effect of Clopidogrel for Prevention of Cardiovascular Events and Bleeding by Patient Group

Endpoint Patients With Event, %

P Value Clopidogrel Placebo

Cardiovascular death, MI, or stroke

All patients 6.8 7.3 .22

No documented CVD (n = 3284) 6.6 5.5 .2

Documented CVD (n = 12,153) 6.9 7.9 .046

Bleeding

Severe, all patients 1.7 1.3 .09

Moderate, all patients 2.1 1.3 < .001

CVD = cardiovascular disease; MI = myocardial infarction

Data from Bhatt, et al.[21]

Clopidogrel is currently the only thienopyridine approved for the treatment of STEMI. Ticlopidine, an early thienopyridine, is

no longer used because the safety profile was worse than that of clopidogrel with no better efficacy.[22]

Two novel adenosine diphosphate-receptor antagonists, prasugrel and ticagrelor, recently completed clinical trials.

Prasugrel was evaluated in TRITON-TIMI 38, which compared prasugrel with clopidogrel in 13,608 patients scheduled to

undergo PCI to treat a moderate-to-severe acute coronary syndrome.[23] The results of a substudy involving only the 3534

patients with STEMI were published by Montalescot and colleagues[24] in 2009. They concluded from the STEMI subgroup

that rates of ischemic events (cardiovascular death, MI, or stroke) were lower with prasugrel than with clopidogrel, with rates

of 10.0% and 12.4%, respectively (hazard ratio, 0.79; 95% CI, 0.65-0.97; P = .0221). Rates of major bleeding in the STEMI

subgroup were similar for the 2 agents, at 2.1% for prasugrel and 2.4% for clopidogrel (P = .6451), although in the overall

trial major bleeding was significantly increased with prasugrel.[24]

Ticagrelor, also known as AZD 6140, has been investigated in the DISPERSE (Dose confIrmation Study assessing anti-

Platelet Effects of AZD6140 vs clopidogRel in non-ST-segment Elevation myocardial infarction) trial. It provided greater

inhibition of platelet aggregation than clopidogrel in patients with acute coronary syndromes not related to STEMI, but it did

not cause significantly greater rates of major bleeding. The study was not designed to determine the efficacy of ticagrelor,

but there appeared to be a trend toward lower rates of cardiovascular death, MI, and stroke with that drug than with

clopidogrel.[25,26] PLATO, a large phase 3 study comparing ticagrelor to clopidogrel in acute coronary syndromes, has recently

been completed and the full results are to be reported soon.[27]

Which intervention would be appropriate if the PCI facility were already in use to treat another patient

and would not be available for another hour? (Assume that the nearest other PCI facility is

approximately 70 minutes away and can be ready within that time.)

Initiate fibrinolytics

Wait for the PCI facility to become available

Transport to the nearest PCI facility

Administer fibrinolytics and then transport for PCI

The timing of reperfusion plays a critical role in treatment decisions. In this situation, fibrinolysis is preferred because the

first- contact-to-balloon time would exceed 90 minutes. Transport to another PCI-equipped facility is a reasonable option to

consider. However, the 70-minute transfer time is also too long in this case.[1]

Almost one fourth of physicians who responded to a survey conducted by Peacock and colleagues[28] were no more than

"somewhat familiar" with the guidelines. About one fifth of the respondents indicated that fibrinolytics were underused -- that

is, that patients who could not receive PCI within 90 minutes and were appropriate candidates for fibrinolysis would rarely if

ever receive fibrinolytic therapy.

The updated ACC/AHA guidelines state that facilitated PCI using full-dose fibrinolytic therapy followed immediately by PCI

may be harmful and is not recommended. Facilitated PCI with lower fibrinolytic dosages might be considered for high-risk

patients (those with large MI or hemodynamic or electrical instability) and for patients at low risk for bleeding when PCI is not

available within 90 minutes.[6]

Facilitated PCI has been investigated in multiple trials, most recently the FINESSE (Facilitated Intervention with Enhanced

Reperfusion Speed to Stop Events) trial reported by Ellis and colleagues[29] in 2008 and in a meta-analysis by Keeley and

colleagues[30] in 2006.

The FINESSE trial evaluated 3 regimens for facilitated PCI: half-dose reteplase in combination with abciximab, abciximab

alone, and primary PCI. The primary endpoint was a composite of death, ventricular fibrillation, cardiogenic shock, and

congestive heart failure.[29] Among the 2452 patients randomized, the primary endpoint occurred within 90 days in 9.8% of

patients in the reteplase plus abciximab group, 10.5% of patients in the abciximab monotherapy group, and 10.7% in the

primary PCI group. These differences were not significant. The hazard ratio for the reteplase plus abciximab group vs the

primary PCI group was 0.81 (95% CI, 0.67-1.23). Bleeding was more significantly common in the reteplase plus abciximab

group than in the primary PCI group. The study authors concluded that the results of the trial did not support facilitated PCI

with the regimens used in the study.

The meta-analysis included 17 trials of 4504 patients who received either facilitated (n = 2237) or primary (n = 2267) PCI. Of

these, 9 trials involved glycoprotein IIb/IIIa inhibitors, 7 involved fibrinolytics, and 2 involved both in combination. Differences

between facilitated and primary PCI in the percentage of patients with final TIMI (Thrombolysis in Myocardial Infarction)

grade 3 flow were not significant (89% with facilitated PCI vs 88% with primary PCI; P = .3).[30] The incidences of mortality,

nonfatal recurrent MI, urgent target-vessel revascularization, and major bleeding were all significantly higher with facilitated

PCI than with primary PCI (Table 6). Most of the increased risk with facilitated PCI was attributed to an increased adverse

event rate in regimens that used thrombolytic therapy rather than glycoprotein IIb/IIIa inhibitors. The study authors

concluded that facilitated PCI offers no benefit over primary PCI and that facilitated PCI with thrombolytic therapy was

associated with increased rates of adverse events and should be avoided.

Table 6. Summary of Outcomes in a Meta-analysis of 17 Trials of Facilitated PCI

Outcome Patients, %

P Value Facilitated PCI Primary PCI

Final TIMI grade 3 flow 89 88 .3

Mortality 5 3 .04

Nonfatal recurrent MI 3 2 .006

Urgent target-vessel revascularization 4 1 .01

Major bleeding 7 5 .01

MI = myocardial infarction; PCI = percutaneous coronary intervention; TIMI = Thrombolysis in Myocardial Infarction

Data from Keeley, et al[30]

The FINESSE trial evaluated 3 regimens for facilitated PCI: half-dose reteplase in combination with abciximab, abciximab

alone, and primary PCI. The primary endpoint was a composite of death, ventricular fibrillation, cardiogenic shock, and

congestive heart failure.[29]Among the 2452 patients randomized, the primary endpoint occurred within 90 days in 9.8% of

patients in the reteplase plus abciximab group, 10.5% of patients in the abciximab monotherapy group, and 10.7% in the

primary PCI group. These differences were not significant. The hazard ratio for the reteplase plus abciximab group vs the

primary PCI group was 0.81 (95% CI, 0.67-1.23). Bleeding was more significantly common in the reteplase plus abciximab

group than in the primary PCI group. The study authors concluded that the results of the trial did not support facilitated PCI

with the regimens used in the study.

Which anticoagulant therapy would have been appropriate if KD had undergone fibrinolytic therapy

instead of PCI?

Enoxaparin

UFH

Fondaparinux

UFH, enoxaparin, or fondaparinux

UFH, enoxaparin, and fondaparinux have all been demonstrated to be effective among patients undergoing reperfusion by

fibrinolysis. Therapy should continue for at least 48 hours and preferably be continued for the duration of the index

hospitalization, with a maximum duration of 8 days. Prolonged therapy with UFH may cause heparin-induced

thrombocytopenia, so other agents should be used if anticoagulant therapy is continued for more than 48 hours. [6] The

recommended dosages are summarized in Table 7.

Table 7. Recommended Dosages for Antithrombotic Agents in STEMI Patients Undergoing Reperfusion by

Fibrinolysis*

UFH

Initial IV bolus 60 U/kg (maximum 4000 U) followed by IV infusion of 12 U/kg/hr (maximum 1000 U/hr)

Adjust to maintain aPTT from 1.5 to 2.0 times control

No benefit to prolonging therapy beyond 48 hours in the absence of ongoing indications

No benefit to prolonging therapy beyond 48 hours in the absence of ongoing indications

Enoxaparin*

For patients with serum creatinine < 2.5 mg/dL (males) or < 2.0 mg/dL (females)

< 75 years of age: Initial IV bolus: 30 mg followed by SC injections of 1.0 mg/kg every 12 hours

Continued for the duration of the index hospitalization with a maximum duration of 8 days

Fondaparinux

For patients with serum creatinine < 3.0 mg/dL

Initial IV dose: 2.5 mg followed by SC injections: 2.5 mg daily

Continued for the duration of the index hospitalization with a maximum duration of 8 days

aPTT = activated partial thromboplastin time; IV = intravenous; SC = subcutaneous; UFH = unfractionated heparin

*For patients of any age, if creatinine clearance using the Cockroft-Gault formula is < 30 mL/min, the SC dose is

1.0 mg/kg every 24 hours.

Data from Antman, et al.[6]

UFH has been used as an antithrombotic for decades and is generally the standard to which newer antithrombotic agents

are compared. Several trials have compared enoxaparin and fondaparinux with UFH.

The EXTRACT-TIMI 28, reported by Antman and colleagues[13] in 2006, is a key comparison of enoxaparin with UFH.

EXTRACT-TIMI 28 randomized 20,506 patients with STEMI to receive either enoxaparin throughout the index hospitalization

or UFH for at least 48 hours. Rates of the primary endpoint (death or nonfatal MI at 30 days) were significantly lower among

patients receiving enoxaparin (9.9%) than among patients receiving UFH (12.0%), with a hazard ratio of 0.83 (95% CI, 0.77-

0.90; P < .001). Rates of the primary endpoint at 8 days and urgent revascularization at 8 days and 30 days were lower with

enoxaparin. Rates of major bleeding were significantly worse among patients receiving enoxaparin than among those

receiving UFH (2.1% vs 1.4%, respectively; P < .001). However, rates of ICH were similar between the groups (0.8% vs

0.7%, respectively; P = .14). In patients who underwent PCI within 30 days after randomization, there was a 23% reduction

in relative risk The study authors concluded that enoxaparin throughout the index hospitalization is superior to UFH for 48

hours as an adjunct to fibrinolytic therapy for STEMI.

The OASIS-6 (Organization for the Assessment of Strategies for Ischemic Syndromes) trial evaluated fondaparinux vs usual

care in 12,092 patients with STEMI.[15] Patients were stratified by whether the investigator judged UFH to be indicated.

Patients for whom UFH was not indicated (stratum 1) were randomized to receive fondaparinux or placebo, while patients for

whom UFH was indicated (stratum 2) received either fondaparinux or UFH. The combined analysis found that fondaparinux

significantly reduced rates of the primary endpoint (death or nonfatal MI at 30 days) compared with usual care (relative risk

reduction, 12%; P = .008). The benefit of fondaparinux was apparent at 9 days after randomization. Fondaparinux was

superior to usual care in both strata but was equivalent to UFH among patients who underwent PCI. Table 8 summarizes the

results for the primary endpoint by strata and timepoint. Rates of bleeding were similar for fondaparinux and UFH in stratum

2. The authors concluded that fondaparinux provides early and persistent reduction in mortality and reinfarction vs usual

care.

Table 8. Efficacy of Fondaparinux vs Usual Care in OASIS-6

Timepoint Stratum Events, n (%)

Hazard Ratio (95% CI) P Value for Interaction †

Usual Care* Fondaparinux

9 days 1 314 (11.1) 239 (8.5) 0.76 (0.64-0.89)

.13 2 223 (6.9) 205 (6.4) 0.92 (0.76-1.11)

30 days 1 396 (14.0) 317 (11.2) 0.79 (0.68-0.92)

.10 2 281 (8.7) 268 (8.3) 0.96 (0.81-1.13)

Study end 1 469 (17.3) 413 (15.9) 0.87 (0.76-0.99)

.88 2 388 (12.7) 343 (11.2) 0.88 (0.76-1.02)

*Usual care was placebo in stratum 1 and unfractionated heparin in stratum 2. † P ≤ .01 required for significance.

Data from Yusuf, et al.[15]

Which duration of clopidogrel therapy would be appropriate if KD had undergone fibrinolytic therapy

instead of PCI?

7 days

14 days to 1 year

Duration of hospital stay

None; clopidogrel should not be administered

The updated ACC/AHA guidelines recommend clopidogrel 75 mg/day in addition to aspirin for patients with STEMI, whether

they receive reperfusion with PCI or fibrinolytics or no reperfusion. For patients receiving fibrinolytics who are younger than

75 years of age, a 300-mg loading dose is reasonable but not specifically recommended. With fibrinolytics, long-term

maintenance therapy with clopidogrel 75 mg/day is also reasonable, although there are no specific recommendations for the

duration of therapy.[6] The recommendations for clopidogrel are based primarily on 2 studies: CLARITY (Clopidogrel as

Adjunctive Reperfusion Therapy)[31] and COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial).[32]

CLARITY compared clopidogrel with placebo in 3491 STEMI patients 75 years of age or younger who received reperfusion

with fibrinolysis. Patients were randomized to receive clopidogrel (300-mg loading dose followed by 75 mg/day) or placebo

and underwent angiography from 48 to 192 hours after starting study medication. The primary endpoint was an occluded

infarct-related artery on angiography or death or MI prior to angiography.[31] Rates of the primary endpoint were 15.0% in the

clopidogrel group and 21.7% in the placebo (relative risk reduction, 36%; 95% CI, 24-47; P < .001). Outcomes were better in

terms of the primary endpoint with clopidogrel for all subgroups (Figure 4). Patients in the clopidogrel group had significantly

better improvement in angiographic measures and lower rates of recurrent MI than patients in the placebo group (P < .001

and P = .02, respectively). Bleeding rates were not significantly different between groups (1.3% clopidogrel vs 1.1% placebo;

P = .64). The study authors recommended clopidogrel to improve rates of infarct artery patency and reduce rates of

ischemic complications.

Figure 4. Efficacy outcomes for clopidogrel vs placebo in the entire patient sample and selected predefined

subgroups in CLARITY.

Adapted from Sabatine, et al.[31]

The larger COMMIT trial compared clopidogrel 75 mg/day with placebo in 45,852 patients with suspected acute MI. No

loading dose was used. STEMI or bundle branch block was present in 93% of the patients enrolled. Clopidogrel significantly

reduced the composite endpoint of death, reinfarction, or stroke (9.2% clopidogrel vs 10.1% placebo; P = .002) and death

from any cause (7.5% clopidogrel vs 8.% placebo; P = .03). Clopidogrel increased the incidence of serious bleeding (fatal,

cerebral, or requiring transfusion) (0.58% clopidogrel vs 0.55% placebo; P = .59). The study authors concluded that

clopidogrel reduces mortality and major vascular event rates without increasing bleeding.

In STEMI patients who are receiving enoxaparin anticoagulant therapy concomitantly with fibrinolytics,

which level of renal impairment requires adjustment of the initial enoxaparin IV bolus dose?

No dose adjustment is needed for renal impairment

Mild (creatinine clearance 50-80 mL/min)

Moderate (creatinine clearance 30-50 mL/min)

Severe (creatinine clearance < 30 mL/min)

The STEEPLE (SafeTy and Efficacy of Enoxaparin in PCI patients, an internationaL randomized Evaluation) trial

investigated the use of IV bolus doses of enoxaparin (0.5 mg/kg or 1.0 mg/kg enoxaparin vs UFH; N = 3528) in patients

undergoing elective PCI. A subanalysis of this trial, reported by White and colleagues[33] in 2009, compared bleeding rates,

achievement of target anticoagulation levels, and rates of a composite of death, nonfatal MI, and urgent target-vessel

revascularization for the 3 treatment regimens and for patients with and without renal impairment (creatinine clearance ≤ 60

mL/min).

Patients without renal impairment were less likely to have major bleeding and were more likely to achieve target

anticoagulation levels than were those with renal impairment. Differences in rates of minor bleeding and the composite

endpoint were not significant.

Among patients with renal impairment, rates of major bleeding were similar for all 3 treatment groups, but significantly more

patients achieved target anticoagulation levels with either dose of enoxaparin than with UFH (Figure 5). Rates of the

composite endpoint of death, nonfatal MI, and urgent target-vessel revascularization were similar for all 3 groups, at 6.2%

for enoxaparin 0.5 mg/kg, 5.3% for enoxaparin 0.75 mg/kg, and 5.6% for UFH (P = .76 and .90 for enoxaparin 0.5 mg/kg and

0.75 mg/kg, respectively, vs UFH).

Figure 5. Rates of major bleeding and achievement of target anticoagulation levels among patients with impaired

renal function.

Adapted from White, et al.[33]

The investigators concluded that enoxaparin provided a more predictable therapeutic response than UFH without increasing

rates of major bleeding.[33] They also concluded that anticoagulant therapy needs to balance the therapy's efficacy in terms of

prevention of ischemic events with the risk for bleeding, and point out that bleeding risk varies across the spectrum of renal

dysfunction.[34]

Case Presentation, Conclusion

KD recovered and was discharged home with a referral to a cardiac rehabilitation program and instructions to continue

clopidogrel for 1 year and aspirin indefinitely, along with her current statin and antihypertensive regimen.

This article is a CME certified activity. To earn credit for this activity visit:

http://cme.medscape.com/viewarticle/706518

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Abstract

RESPUESTAS CORRECTAS

What is the appropriate next action for this patient?

Perform 12-lead electrocardiography (ECG)

KD's chest pain is suggestive of a possible ST-segment elevation myocardial infarction (STEMI). Thus, a 12-lead ECG should be obtained within 10 minutes of the patient's arrival at the emergency department. The other actions listed, while important for diagnosis and management, should not delay the ECG.

By what percentage does a 30-minute delay in reperfusion increase 1-year mortality in patients with

STEMI?

7.5%

Current therapies for reperfusion of patients with STEMI need to be instituted rapidly after the onset of symptoms to be optimally efficacious. Every minute of delay increases mortality; a 30-minute delay increases mortality by 7.5%.

Which statement correctly describes patients with STEMI who present with atypical or typical

symptoms?

Approximately 8% of STEMI patients present with atypical symptoms (ie, no chest pain or

discomfort)

Approximately 8% (1 in 13) of patients with STEMI present without chest pain or discomfort. These patients are less likely to be initially diagnosed as having STEMI and have a worse prognosis than those who present with typical symptoms.

What is the appropriate next action for this patient?

Activate the PCI facility

The ECG is sufficient for a diagnosis of STEMI. Thus, reperfusion is the next step and confirmatory testing should not delay reperfusion. The updated ACC/AHA STEMI guidelines recommend reperfusion with PCI for patients with STEMI if it can be provided within 90 minutes of presentation.

Which conditions are considered absolute contraindications to fibrinolytic therapy?

History of intracranial hemorrhage (ICH) or recent internal bleeding

Any history of ICH or a recent history of ischemic stroke is an absolute contraindication to fibrinolytics because this indicates increased risk for ICH, a serious risk of fibrinolytic therapy. Recent internal bleeding and uncontrolled hypertension are relative contraindications.

Which biomarker should be assessed after activation of the PCI facility?

Cardiac troponins

Troponins are the preferred biomarker for diagnosing MI because of their high specificity and sensitivity for myocardial necrosis.

On the basis of clinical evidence, which statement correctly describes anticoagulant therapy in PCI

patients?

Patients taking enoxaparin (vs unfractionated heparin [UFH]) are more likely to reach

anticoagulation levels

The ACC/AHA STEMI guidelines recommend UFH for patients undergoing PCI or surgical revascularization.

Which antiplatelet therapy would be appropriate for KD?

Aspirin and clopidogrel in combination

All patients with STEMI should receive the combination of aspirin and clopidogrel unless contraindications are present.

Which intervention would be appropriate if the PCI facility were already in use to treat another patient

and would not be available for another hour? (Assume that the nearest other PCI facility is

approximately 70 minutes away and can be ready within that time.)

Initiate fibrinolytics

Which anticoagulant therapy would have been appropriate if KD had undergone fibrinolytic therapy

instead of PCI?

UFH, enoxaparin, or fondaparinux

UFH, enoxaparin, and fondaparinux all have established efficacy in STEMI patients undergoing reperfusion with fibrinolysis. The ACC/AHA guidelines do not express a preference for any of these agents, aside from stating that UFH is not recommended if treatment duration will exceed 48 hours.

Which duration of clopidogrel therapy would be appropriate if KD had undergone fibrinolytic therapy

instead of PCI?

14 days to 1 year

The ACC/AHA guidelines recommend continuing aspirin indefinitely and clopidogrel for at least 14 days.

In STEMI patients who are receiving enoxaparin anticoagulant therapy concomitantly with fibrinolytics,

which level of renal impairment requires adjustment of the initial enoxaparin IV bolus dose?

No dose adjustment is needed for renal impairment

The ACC/AHA guidelines do not recommend any change in the IV bolus dose of enoxaparin based on renal impairment, although they do recommend reducing the subcutaneous doses that follow to 1 mg/kg/day for patients with severe renal impairment (creatinine clearance < 30 mL/min).