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Chapter 146 Acute Coronary Syndromes 2145

Case 1: Bleeding After Fibrinolytic Therapy
A 63-year-old man with a history of hypertension presents to a rural bleeding; (3) draw blood to measure fibrinogen, prothrombin time (PT),
hospital with sudden onset of severe retrosternal chest pain. An electro- aPTT, and possibly anti-Xa levels (to measure the anticoagulant effect of
cardiogram (ECG) performed in the emergency department demonstrates low-molecular-weight heparin [LMWH]) and for blood typing and cross-
4-mm ST segment elevation in the anterior leads. The nearest hospital match; and (4) administer therapies to mitigate or reverse the effects of
with a cardiac catheterization laboratory is more than 6 hours away. fibrinolytic, antiplatelet, and anticoagulant drugs.
After treatment with aspirin (300 mg loading dose), clopidogrel (300 mg The extent and duration of the systemic lytic state induced by fibrinolytic
loading dose), and an intravenous (IV) infusion of front-loaded alteplase, drugs are determined by their fibrin specificity. Whereas streptokinase
he has rapid resolution of his pain and the ECG reveals normalization produces profound and sustained depletion of fibrinogen (<100 mg/dL)
of the ST-segment elevation. Toward the end of the alteplase infusion, that lasts for up to 24–48 hours, alteplase and other more fibrin-specific
he complains of abdominal pain, becomes hypotensive, and develops agents exert less pronounced and more short-lived effects on fibrinogen
melena. Hemoglobin is 10.2 g/dL, the activated partial thromboplastin levels. The aPTT and PT can be markedly prolonged in patients with
time (aPTT) is 89 seconds, the international normalized ratio (INR) is hypofibrinogenemia. Normal coagulation can be restored by elevating the
1.7, and the fibrinogen level is 80 mg/dL. fibrinogen level to at least 100 mg/dL. This can readily be achieved by
Aspirin and clopidogrel are held; the patient receives 10 units of cryo- infusing cryoprecipitate (recommended dose: 10 units). Although fresh
precipitate and is started on an IV infusion of a proton pump inhibitor. He frozen plasma also contains fibrinogen, much larger volumes are needed
undergoes urgent upper gastrointestinal tract endoscopy with injection to increase the fibrinogen concentration to the desired range.
of a bleeding ulcer. He does not receive platelets because of concerns Platelet dysfunction caused by aspirin, clopidogrel, and fibrinolytic
about the risk of recurrent myocardial infarction (MI). No further bleeding therapy cannot be specifically reversed, but infusion of donor platelets
occurs, and after 48 hours he resumes aspirin. Clopidogrel is restarted can help to restore platelet function. Platelet transfusion is generally
1 week later after repeat endoscopy demonstrates healing of the ulcer. reserved for patients with life-threatening bleeding because of concerns
about the risk of recurrent MI. A single unit of single donor platelets can
Comment be expected to increase the platelet count by 50–60 × 10 /L. Even a
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Fibrinolytic trials in patients with acute MI report a 1%–6% incidence small number (e.g., 10%–20%) of functional (nonaspirinated) platelets
of major bleeding and a 10% incidence of moderate bleeding during is sufficient to generate sufficient thromboxane to sustain normal platelet
the first 30 days. The most common sources of major bleeding are the aggregation, but a much larger number of transfused platelets is needed
gastrointestinal tract and procedure-related bleeding. The principles of to overcome the antiplatelet effects of clopidogrel. In this case, bleeding
management of major bleeding in STEMI patients treated with fibrinolytic was controlled with cryoprecipitate and local measures, and platelet
therapy are summarized in Table 146.2. Steps include (1) stop anti- transfusion was not required.
thrombotic therapies; (2) use local measures when possible to control

TABLE Pharmacologic Characteristics of Oral Antiplatelet Drugs Commonly Used in the Management of Acute Coronary Syndromes
146.3
ADP Receptor Antagonists
Characteristic Aspirin Clopidogrel Prasugrel Ticagrelor
Class COX inhibitor Thienopyridine (second Thienopyridine (third Cyclopentyl triazolopyrimidine
generation) generation)
Target COX-1 P2Y12 P2Y12 P2Y12
Dose 162–325-mg loading 300–600-mg loading dose; 60-mg loading dose; 180-mg loading dose; 90 mg
dose; 75–325 mg/day 75 mg/day maintenance 10 mg/day bid maintenance dose
maintenance dose dose maintenance dose
Prodrug No Yes Yes No
Time to effect a <1 hour 4–6 hours b <1 hour <1 hour
Drug half-life 20 min Minutes Minutes 12 hours
Reversible No No No Yes
a After loading dose.
b Increased antithrombotic benefit was seen after the first hour in patients enrolled in the COMMIT trial who did not receive a loading dose, but maximum effect is not
seen until after 4–6 hours.
ADP, Adenosine diphosphate; bid, twice daily; COX, cyclooxygenase.

At least four randomized controlled trials have demonstrated the ACS patients with or without ST-segment elevation on the presenting
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efficacy of aspirin in patients with NSTE ACS. Pooled data from four ECG and included 17,263 patients undergoing early PCI. After an
trials that included a combined total of 3096 patients indicate that initial aspirin loading dose, patients were randomized to receive
aspirin compared with placebo or no aspirin significantly reduced the aspirin at a dose of 300–325 mg/day or 75–100 mg/day for 30 days.
composite endpoint of MI, stroke, or vascular death (6.4% vs. 12.5%; The two doses were associated with similar rates of MI, stroke, or
p = .0005). death at 30 days (4.2% vs. 4.4%), but the higher aspirin dose
The efficacy and safety of aspirin in combination with dipyridam- increased the rate of gastrointestinal bleeding (0.4% vs. 0.2%;
ole have been evaluated in PCI patients in one randomized controlled p = .04). Based on these results, the optimal dose of aspirin for the
trial involving 376 patients. Aspirin (300 mg) plus dipyridamole management of patients with ACS (after an initial loading dose of
(75 mg given three-times daily except during a 24-hour period 160–325 mg) appears to be 75–100 mg/day.
around the time of the procedure when dipyridamole was given
intravenously) reduced the risk of MI by more than half compared
with placebo (1.6% vs. 6.9%; p = .01). These results led to the Clopidogrel
adoption of aspirin as standard therapy for patients undergoing PCI.
The CURRENT OASIS-7 (Clopidogrel Optimal Loading Dose Clopidogrel undergoes metabolic activation in the liver to form the
Usage to Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy active moiety that irreversibly blocks P2Y12, the major ADP receptor
for InterventionS) trial explored the optimal dose of aspirin in 25,086 on the platelet surface as evidenced by a decrease in ADP-induced