Page 2405 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 146 Acute Coronary Syndromes 2147

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p = .015). Pooled data from a meta-analysis of 16 randomized trials ANTICOAGULANT THERAPY
involving 10,085 STEMI patients undergoing primary PCI demon-
strated that adjunctive GP IIb/IIIa blockade did not reduce 30-day Anticoagulant therapy is effective for the initial and long-term
mortality (2.8 vs. 2.9%; p = .75) or reinfarction (1.5 vs. 1.9%; management of patients with ACS with or without ST-segment eleva-
p = .22) and increased major bleeding (4.1 vs. 2.7%; p = .0004). tion. 5,6,10 The pharmacologic characteristics of parenteral anticoagu-
However, meta–regression analysis confirmed the impression from lants commonly used in the management of ACS are summarized in
individual trials of a mortality benefit of IV GP IIb/IIIa inhibitors in Table 146.5. Early trials suggested that heparin and aspirin were
those at highest risk (see boxes on Case 2: Stent Thrombosis and Case similarly effective for the prevention of MI, but aspirin was adopted
3: Thrombocytopenia After Stenting). 20 as the foundation antithrombotic therapy because it caused less bleed-
ing than heparin. Subsequent randomized controlled trials demon-
strated that the combination of heparin plus aspirin provided additive
Cangrelor benefit. More recent trials have established the efficacy and safety of
newer parenteral anticoagulants, including low-molecular-weight
Cangrelor is an IV P2Y12 receptor antagonist that has been compared heparin (LMWH), fondaparinux, and bivalirudin, on a background
with clopidogrel or placebo in three randomized trials that included of single- or dual-agent antiplatelet therapy for the initial manage-
patients with NSTE ACS. An individual patient metaanalysis of the ment of patients with ACS.
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three trials demonstrated that compared with control, cangrelor The pharmacologic characteristics of warfarin and new oral anti-
reduced the risk of ischemia-driven revascularization, stent thrombo- coagulants evaluated in the management of ACS are summarized
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sis, MI or death at 48 hours (3.8% vs. 4.7%, p = .0007) at the in Table 146.6. Warfarin is effective for the prevention of major
cost of an increase in GUSTO mild bleeding (16.8% vs. 13.0%, cardiovascular events for the long-term management of patients with
p < .0001) but no increase in more severe bleeding. ACS who are also treated with aspirin, but no adequately powered
randomized controlled trials have evaluated the efficacy and safety of
warfarin in the context of dual antiplatelet therapy. Two new oral anti-
Case 2: Stent Thrombosis coagulants (rivaroxaban and apixaban) have been evaluated in phase
A 49-year-old man with a history of type 2 diabetes presents with III trials for long-term secondary prevention in ACS patients, 26,27 and
non–ST-segment elevation myocardial infarction and undergoes rivaroxaban has been approved for this indication in Europe.
percutaneous coronary intervention (PCI) with placement of a drug-
eluting stent in the left anterior descending coronary artery. He receives
a 300-mg loading dose of aspirin and a 600-mg loading dose of Heparin
clopidogrel and is discharged on aspirin 100 mg/day and clopidogrel
75 mg/day. He presents to the emergency department 3 weeks later Heparin is derived from porcine intestinal mucosa and is administered
with recurrent chest pain and anterior ST-segment elevation on the by IV or subcutaneous injection. It inhibits coagulation by binding
electrocardiogram. He denies missing any doses of clopidogrel. He
is taken urgently to the cardiac catheterization laboratory where a
diagnosis of stent thrombosis is confirmed, and he undergoes repeat
PCI with thrombus aspiration. Case 3: Thrombocytopenia After Stenting
Prompted by concern about the possibility of “clopidogrel resistance”,
genotyping studies are performed and demonstrate heterozygosity for A 65-year-old woman presenting with ST-segment elevation myocardial
the CYP2C19 *2 loss-of-function allele. Clopidogrel is stopped, and he infarction undergoes primary percutaneous coronary intervention with
is started on prasugrel (10 mg once daily) instead. He is discharged on placement of a bare metal stent in her circumflex coronary artery.
indefinite dual antiplatelet therapy with aspirin and prasugrel. During the procedure, she receives an intravenous bolus of abciximab
in addition to aspirin, clopidogrel, and heparin. A blood count per-
Comment formed after returning to the coronary care unit (within 6 hours of the
Stent thrombosis is a potentially life-threatening complication of PCI, procedure) reveals a platelet count of 6 × 10 /L, which is confirmed on
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affecting 1%–2% of patients during the first year and presenting repeat testing using a sample collected in sodium citrate (to eliminate
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in almost all cases as death or myocardial infarction. Risk factors platelet clumping as a cause of spurious thrombocytopenia). She is
for stent thrombosis can be categorized as patient related, techni- diagnosed with abciximab-induced thrombocytopenia.
cal (procedure, stent, or lesion), or drug related. The single most Heparin is stopped, and the patient receives 1 unit of single-donor
important predictor of stent thrombosis is premature discontinuation platelets with a prompt increase in her platelet count. She is continued
of clopidogrel. High on-treatment platelet reactivity during clopidogrel on aspirin and clopidogrel and is started on a proton pump inhibitor.
therapy has also emerged as a predictor of stent thrombosis and is The platelet count begins to rise spontaneously on day 4 and returns
affected by clinical (e.g., age, diabetes, renal insufficiency) and genetic to baseline levels within 1 week.
factors. Carriers of reduced-function CYP2C19 alleles have low levels
of the active metabolite of clopidogrel, diminished platelet inhibition, Comment
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and an increased risk of stent thrombosis. Unlike clopidogrel, which Severe thrombocytopenia (platelet count <50 × 10 /L) occurs in about
undergoes two-step, cytochrome P450 (CYP)–dependent metabolic 0.5% and less severe thrombocytopenia in 2%–4% of patients treated
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bioconversion in the liver, prasugrel and ticagrelor are not affected with glycoprotein (GP) IIb/IIIa inhibitors. Thrombocytopenia caused by
by CYP polymorphisms and consistently produce greater and more GP IIb/IIIa inhibitors is readily distinguished from other causes by its
consistent inhibition of ADP-induced platelet aggregation than standard rapid onset, typically within 24 hours of exposure and sometimes within
doses of clopidogrel. Higher doses of clopidogrel (e.g., 225 or 300 mg/ with first hour, and severity (count often <10 × 10 /L). By contrast,
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day) in patients heterozygous for CYP2C19*2 alleles produce levels of heparin-induced thrombocytopenia is usually delayed until at least 4
platelet inhibition similar to those seen with standard (75 mg) doses days after starting heparin therapy (with the exception of patients with
but have not been evaluated in clinical outcome studies. prior exposure to heparin in the past 3 months) and platelet counts
The role of genetic testing to detect poor clopidogrel responders rarely fall below 30 × 10 /L. The rapid onset of thrombocytopenia is
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remains controversial. Although observational studies have demon- believed to be caused by preformed antibodies that react with GP IIb/IIIa
strated an independent association between CYP2C19 loss-of-function inhibitor-coated platelets. Spontaneous recovery of the platelet count
alleles and the risk of stent thrombosis, analyses from multiple random- usually occurs within days but can take several weeks. Patients with GP
ized controlled trials provide no evidence of an interaction between IIb/IIIa inhibitor–induced thrombocytopenia respond normally to platelet
genotype and treatment for major cardiovascular events, including transfusions, which should be considered when the count is below 10 ×
stent thrombosis. It is reasonable to switch patients who have experi- 10 /L to reduce the risk of spontaneous bleeding. There is no evidence
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enced stent thrombosis despite clopidogrel therapy to one of the newer that steroids or IV gamma globulin alter the natural history of GP IIb/
P2Y12 receptor antagonists (i.e., prasugrel or ticagrelor) that have been IIIa inhibitor-induced thrombocytopenia. Repeated exposure to GP IIb/
demonstrated to reduce the risk of stent thrombosis compared with IIIa inhibitors should be avoided because there is a risk of recurrent
clopidogrel even without laboratory testing. thrombocytopenia, which may be more severe than the initial episode.