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2296 Part XII: Hemostasis and Thrombosis Chapter 134: Atherothrombosis: Disease Initiation, Progression, and Treatment 2297

infusion with monitoring of the activated partial thromboplastin time and clopidogrel. However, the combination was associated with an
240
(aPTT) measured at 6 hours. The heparin dose is adjusted to maintain increase in major bleeding and reoperation for bleeding in patients
an aPTT between 50 and 75 seconds. who underwent coronary artery bypass grafting (CABG). Therefore, a
Current guidelines recommend maintaining the aPTT at 50 to 5-day, but preferably a 7-day, period off clopidogrel is recommended
75 seconds for short-term use. Heparin should be continued beyond before CABG. 241
this period only in the case of high risk of systemic or venous thrombo- A meta-analysis of randomized clinical trials found that intra-
embolism. Patients can be switched to a subcutaneously administered venous platelet integrin IIb/IIIa inhibitors substantially benefited
heparin or converted to oral warfarin during the high-risk period. The patients with non–ST-segment elevation ACS undergoing coronary
anticoagulant drugs unfractionated heparin, enoxaparin, fondaparinux, intervention. The integrin α β receptor antagonist abciximab
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IIb IIIa
and bivalirudin are all excreted by the kidneys; consequently, although (ReoPro) is a monoclonal antibody fragment that reduces short-term
the first dose is usually safe, longer-term therapy should be guided by and long-term clinical events in patients with ACS undergoing angio-
assessment of creatinine clearance. The Coumadin-Aspirin Reinfarc- plasty with or without stent placement. Other platelet integrin α β
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IIb IIIa
tion Study (CARS) did not show a significant benefit with the combina- antagonists, such as tirofiban and Integrilin, also are effective and
tion of low-dose warfarin (1 or 3 mg) and aspirin 80 mg daily compared safe in treating unstable angina when combined with heparin anti-
to aspirin 160 mg daily monotherapy on cardiovascular morbidity in coagulation. Guidelines from an ACC/AHA task force recommend
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patients who had an MI. 231 administration of an integrin α β inhibitor, in addition to aspirin
IIb IIIa
Statins All patients with MI should be started on a 3-hydroxy- and heparin, for patients with unstable angina/NSTEMI undergoing
3-methylglutaryl-coenzyme A reductase inhibitor (statin) unless the planned PCI. 220
MI was caused by a nonatherosclerotic process such as coronary vaso- Unfractionated heparin reduces the rate of MI and death, and
spasm, vasculitis, or embolus. Numerous studies indicate that statins relieves anginal pain, when used in combination with an antiplatelet
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reduce the risk of subsequent MI by approximately 30 to 50 percent. agent. Intravenous heparin usually is given as a 5000-U bolus fol-
Current evidence suggests that a serum LDL level less than 80 mg/dL lowed by continuous infusion. Low-molecular-weight heparins can
with statin treatment is more efficacious in retarding atherosclerotic be substituted for unfractionated heparin. Some studies have shown
disease progression than a serum LDL level of 100 mg/dL or above. superior efficacy of low-molecular-weight heparins, but other studies
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Other nonstatin drugs, such as ezetimibe, PCSK9 inhibitors, and have not indicated a significant difference. Direct thrombin inhibi-
microsomal triglyceride transfer protein inhibitors, also reduce choles- tors, such as hirudin and bivalirudin, have been shown to reduce the
terol levels but relative reduction in cardiovascular events compared to rate of death, nonfatal MI, and refractory angina compared to hepa-
statins is not yet clear. rin. 244,245 The American College of Chest Physicians (ACCP) recom-
Therapy for Unstable Angina Pectoris and Non–ST-Elevation mends lepirudin (recombinant hirudin), argatroban, bivalirudin, or
Myocardial Infarction The distinction between unstable angina and danaparoid in patients with a history of heparin-associated thrombo-
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NSTEMI initially may be difficult because levels of troponins and/or cytopenia, although some of these agents are no longer available in
CK-MB may not be elevated until hours after presentation. Similar to the United States.
STEMI, the initial treatment of unstable angina and NSTEMI includes Therapy for Stable Angina Pectoris Patients with stable angina
supplemental oxygen, pain control, and bed rest. Nitrates, given either pectoris can be treated with either medical management or revasculari-
230
intravenously or subcutaneously, are the treatment of choice for angina zation. Limited clinical trial data comparing revascularization, either
247
pectoris. Oral β-blockers also are routinely given to patients with unsta- percutaneous or surgical, to medical therapy are available. The older
ble angina to relieve symptoms of angina and to reduce the risk of pro- trials evaluating percutaneous and surgical revascularization were lim-
gression to MI. ited by several factors: antiplatelet treatment, angiotensin-converting
Treatment of unstable angina and NSTEMI involves administra- enzyme inhibitors, and aggressive lipid lowering with statins were not
tion of an antiplatelet agent and anticoagulation. Fibrinolytic therapy given as background medical therapy of angina. Given these limitations,
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is not beneficial in patients with unstable angina, and its use is asso- determining whether revascularization is better than medical manage-
ciated with unacceptably high bleeding risk. Antiplatelet treatment, ment for long-term care of patients with stable angina in modern prac-
most commonly aspirin at a dose of 325 mg daily, was shown in the tice is difficult.
Antithrombotic Trialists’ Collaboration to reduce the combined end Both PCI and coronary bypass surgery significantly reduce
point of subsequent nonfatal MI, nonfatal stroke, or vascular death angina. The Coronary Artery Surgery Study (CASS) showed more
(8.0 percent vs. 13.3 percent) in patients with non–ST-segment eleva- patients remained symptom-free after CABG compared to medical
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tion ACS. Clinical trials involving patients with non–ST-segment therapy 5 years after the procedure. At 10 years, however, no sig-
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elevation ACS have demonstrated significantly reduced cardiovascular nificant difference in symptoms was observed. Clinical trials showed
events and mortality with aspirin administration, mostly at a lower dose significant improvement in angina with PCI compared to medical
of 80 to 100 mg orally once per day. 235–237 Some patients do not benefit therapy; however, patients who underwent the former had similar
from aspirin, and this finding has generated an interest as to whether rates of death and MI as those undergoing medical therapy and were
these patients are “aspirin resistant.” Nonrandomized studies indicate less likely to have angina and more likely to have undergone a coro-
that aspirin resistance may occur, but because of the limitations of these nary bypass graft. 249
studies, the definition and prognostic significance of this phenomenon Restenosis is a complex process involving inflammation, cellular
are uncertain. 238 proliferation, thrombosis, and matrix deposition. Restenosis occur-
The thienopyridine clopidogrel (75 mg/day) is effective in reduc- ring after PCI may result in flow-limiting luminal narrowing in 20 to
250
220
ing the risk of MI and mortality in patients with unstable angina. 30 percent of therapeutically dilated vessels. Numerous pharma-
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The combination of aspirin and clopidogrel has been tested in patients cologic agents, including heparin, have been given in an attempt
with NSTEMI and unstable angina. The combination of these anti- to reduce the restenosis rate but have met with limited or no success.
platelet agents resulted in improved survival and decreased progres- Intraarterial radiation (brachytherapy) reduces the restenosis rate
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sion to MI. The patients with non–ST-segment elevation ACS who but is cumbersome to perform because of radiation safety issues and
underwent PCI benefited the most from the combination of aspirin has fallen out of favor. Drug-eluting arterial stents, including the

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