Acute Coronary Syndromes

Published on 04/03/2015 by admin

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Chapter 65 Acute Coronary Syndromes

Table 65-1 Pharmacologic Characteristics of Fibrinolytic Drugs Used in the Management of Patients With ST-Segment Elevation Myocardial Infarction

* Less fibrin specificity is associated with more systemic fibrinogen depletion.

† Fibrinolytic drugs were evaluated on a background of aspirin, but the addition of clopidogrel to aspirin was subsequently shown to provide incremental benefit.

‡ High-risk patients include those with large or anterior myocardial infarction, atrial fibrillation, known left ventricular thrombus, or previous thromboembolism.

Case 1: Bleeding After Fibrinolytic Therapy

A 63-year-old man with a history of hypertension presents to a rural hospital with sudden onset of severe retrosternal chest pain. An ECG performed in the emergency department demonstrates 4-mm anterior ST segment elevation. The nearest hospital with a cardiac catheterization laboratory is more than 6 hours away. He is treated with aspirin (300 mg loading dose), clopidogrel (300 mg loading dose), and an IV infusion of front-loaded alteplase, with rapid resolution of pain and normalization of ST-segment elevation. Toward the end of the alteplase infusion, he complains of abdominal pain, becomes hypotensive, and develops melena. Hemoglobin is 10.2 g/dL, the aPTT is 89 seconds, the international normalized ratio (INR) is 1.7, and the fibrinogen level is below 100 mg/dL.

Aspirin and clopidogrel are held; the patient receives 10 units of cryoprecipitate and is started on an IV infusion of a proton pump inhibitor. He undergoes urgent upper gastrointestinal tract endoscopy with injection of a bleeding ulcer. He does not receive platelets because of concerns about the risk of recurrent MI. No further bleeding occurs, and after 48 hours, he resumes aspirin. Clopidogrel is restarted 1 week later after repeat endoscopy demonstrates a healing ulcer.

Comment

Fibrinolytic trials report a 1% to 6% incidence of major bleeding and a 10% incidence of moderate bleeding during the first 30 days. The most common sources of major bleeding are the gastrointestinal tract and procedure-related bleeding. The principles of management of major bleeding in STEMI patients treated with fibrinolytic therapy are summarized in Table 65-2. Steps include (1) stop antithrombotic therapies; (2) use local measures when possible to control bleeding; (3) draw blood to measure fibrinogen, prothrombin time (PT), aPTT, and possibly anti-Xa levels (to measure the anticoagulant effect of low-molecular-weight heparin) and to crossmatch blood; and (4) administer therapies to mitigate or reverse the effects of fibrinolytic, antiplatelet, and anticoagulant drugs.

The extent and duration of the lytic effects of fibrinolytic drugs is determined by their fibrin specificity. Whereas streptokinase produces profound and sustained depletion of fibrinogen (<100 mg/dL) that lasts for up to 24 to 48 hours, alteplase and other more fibrin-specific agents exert a less pronounced and more short-lived effect on fibrinogen levels. The aPTT and PT can be markedly prolonged in patients with hypofibrinogenemia. Normal coagulation can be restored by elevating fibrinogen level to at least 100 mg/dL. This can be readily achieved by infusing cryoprecipitate (recommended dose, 10 units). Fresh-frozen plasma also contains fibrinogen but requires administration of much larger volumes.

Platelet dysfunction caused by aspirin, clopidogrel, and fibrinolytic therapy cannot be specifically reversed, but infusion of donor platelets can help to restore platelet function. Platelet transfusion is generally reserved for patients with life-threatening bleeding because of concerns about the risk of recurrent MI. A single unit of single donor platelets can be expected to increase the platelet count by 50 to 60 × 10⁹/L. Even a small number (e.g., 10%-20%) of functional (nonaspirinated) platelets are sufficient to generate sufficient thromboxane to sustain normal platelet aggregation, but a much larger number of transfused platelets are need to overcome the antiplatelet effects of clopidogrel. In this case, bleeding was controlled with cryoprecipitate, and local measures and platelet infusions were not required.

Table 65-2 Management of Major Bleeding in Patients With ST-Segment Elevation Myocardial Infarction Treated With Fibrinolytic Therapy

aPTT, Activated partial thromboplastin time; FFP, fresh-frozen plasma; GI, gastrointestinal; INR, international normalized ratio; LMWH, low-molecular-weight heparin; PT, prothrombin time

* Also requires restoration of adequate hemostasis.

Table 65-3 Pharmacologic Characteristics of Oral Antiplatelet Drugs Commonly Used in the Management of Acute Coronary Syndromes

ADP, Adenosine diphosphate; bid, twice daily; COX, cyclooxygenase.

* After loading dose.

† 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 to 6 hours.

Table 65-4 Pharmacologic Characteristics of Intravenous Glycoprotein IIb/IIIa Inhibitors Used in the Management of Acute Coronary Syndrome

Case 2: Stent Thrombosis

A 49-year-old man with a history of type 2 diabetes presents with NSTEMI and undergoes 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 clopidogrel and is discharged on aspirin 100 mg/day and clopidogrel 75 mg/day. He presents to the emergency department 3 weeks later with recurrent chest pain and anterior ST-segment elevation on the ECG. 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.

Prompted by concern about the possibility of “clopidogrel resistance,” genotyping studies are performed and demonstrate heterozygosity for the CYP2C19 *2 loss-of-function allele. Clopidogrel is stopped, and he is started on prasugrel (10 mg once daily) instead. He is discharged on indefinite dual antiplatelet therapy with aspirin and prasugrel.

Stent thrombosis is a potentially life-threatening complication of PCI, affecting 1% to 2% of patients during the first year and presenting in almost all cases as death or MI.¹ Risk factors for stent thrombosis can be categorized as patient related, technical (procedure, stent, or lesion), or drug related. The single most important predictor of stent thrombosis is premature discontinuation of clopidogrel. High on-treatment platelet reactivity during clopidogrel therapy has also emerged as a predictor of stent thrombosis and is affected by clinical (e.g., age, diabetes, renal insufficiency) and genetic factors. Carriers of reduced function CYP2C19 alleles have low levels of the active metabolite of clopidogrel, diminished platelet inhibition, and an increased risk of stent thrombosis. Unlike clopidogrel, which undergoes two-step, cytochrome P450-dependen, metabolic conversion in the liver, prasugrel and ticagrelor are not affected by CYP polymorphisms and consistently produce a greater and more consistent level of platelet inhibition than standard clopidogrel doses. Higher doses of clopidogrel (e.g., 225 or 300 mg/day) in patients heterozygous for CYP2C19*2 alleles achieve levels of platelet inhibition similar to those seen with standard (75 mg) doses but have not been evaluated in clinical outcome studies.

The role of genetic testing to detect poor clopidogrel responders remains controversial. Although observational studies have demonstrated an independent association between CYP2C19 loss-of-function alleles and risk of stent thrombosis, analyses from multiple randomized controlled trials provide no evidence of an interaction between genotype and treatment for major cardiovascular events, including stent thrombosis. It is reasonable to switch (without laboratory testing) patients who have experienced stent thrombosis despite clopidogrel therapy to one of the newer P2Y12 receptor antagonists (i.e., prasugrel or ticagrelor) that have been demonstrated to reduce the risk of stent thrombosis compared with clopidogrel.

Case 3: Thrombocytopenia After Stenting

A 65-year-old woman presenting with STEMI undergoes primary PCI with placement of a bare metal stent in her circumflex coronary artery. During the procedure, she receives an IV bolus of abciximab in addition to aspirin, clopidogrel, and heparin. A blood count performed after returning to the coronary care unit (within 6 hours of the procedure) reveals a platelet count of 6 × 10⁹/L, which is confirmed on repeat testing using a sample collected in sodium citrate (to eliminate platelet clumping as a cause of spurious thrombocytopenia). She is diagnosed with abciximab-induced thrombocytopenia.

Heparin is stopped, and the patient receives 1 unit of single donor platelets with a prompt increase in her platelet count. She is continued on aspirin and clopidogrel and is started in a proton pump inhibitor. The platelet count begins to rise spontaneously on day 4 and returns to baseline levels within 1 week.

Comment

Severe thrombocytopenia (platelet count <50 × 10⁹/L) occurs in about 0.5% and less severe thrombocytopenia in 2% to 4% of patients treated with GP IIb/IIIa inhibitors.³ Thrombocytopenia caused by GP IIb/IIIa inhibitors is readily distinguished from other causes by its rapid onset, typically within 24 hours of exposure and sometimes within with first hour, and severity (count often <10 × 10⁹/L). By contrast, heparin-induced thrombocytopenia is usually delayed until at least 4 days after starting heparin therapy (with the exception of patients with prior exposure to heparin in the past 3 months) and platelet counts rarely fall below 30 × 10⁹/L. The very rapid onset of thrombocytopenia is believed to be caused by preformed antibodies that react with GP IIb/IIIa inhibitor–coated platelets. Spontaneous recovery of the platelet count usually occurs within days but can take several weeks. Patients with GP IIb/IIIa inhibitor–induced thrombocytopenia respond normally to platelet transfusions, which should be considered when the count is below 10 × 10⁹/L to reduce the risk of spontaneous bleeding. There is no evidence that steroids or IV gamma globulin alter the natural history of GP IIb/IIIa inhibitor–induced thrombocytopenia. Repeated exposure to GP IIb/IIIa inhibitors should be avoided because there is a risk of recurrent thrombocytopenia, which may be more severe than the initial episode.

Table 65-5 Pharmacologic Characteristics of Parenteral Anticoagulants Commonly Used in the Management of Patients With Acute Coronary Syndromes

ACS, acute coronary syndromes; aPTT, activated partial thromboplastin time; CrCl, creatinine clearance; HIT, heparin-induced thrombocytopenia; IV, intravenous; SC, subcutaneous.

* The first dose of enoxaparin was given by the intravenous route in the TIMI-11B (Thrombolysis In Myocardial Infarction 11B) and EXTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment, Thrombolysis in Myocardial Infarction 25) studies. The first dose of fondaparinux was given by the intravenous route in the OASIS-6 (Optimal Antiplatelet Strategy for InterventionS 6) trial.

† Acute coronary syndrome patients with creatinine up to 265 µmol/L were eligible for inclusion in the OASIS-5 and -6 trials (equivalent to an estimated creatinine clearance of 15 to 20 mL/min in a 70-kg patient who is 70 years of age).

‡ Fondaparinux is contraindicated in patients with venous thromboembolism who have severe renal impairment.

§ Monitoring and dose adjustment required in patients with creatinine clearance below 30 mL/min.

Table 65-6 Pharmacological Characteristics of Warfarin and New Oral Anticoagulants Evaluated in Phase 3 Trials for the Long-Term Management of Acute Coronary Syndromes

CYP-3A4, Cytochrome p-450 3A4; FFP, fresh-frozen plasma; fXa, activated factor X; INR, international normalized ratio; PCC, prothrombin complex concentrates; P-gp, P-glycoprotein; VKOR, vitamin K epoxide reductase.

* A once-daily regimen was tested in atrial fibrillation.

† Half of renally cleared rivaroxaban is cleared as unchanged drug and half as inactive metabolites.

‡ Potent inhibitors of both CYP3A4 and P-glycoprotein include azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) and protease inhibitors, such as ritonavir. Potent inhibitors of CYP3A4 include azole antifungals, macrolide antibiotics (e.g., clarithromycin), and protease inhibitors (e.g., atanazavir).

Table 65-7 Strategies Aimed at Minimizing the Risk of Bleeding in Patients Treated With Triple Therapy (Dual Antiplatelet Therapy and an Oral Anticoagulant)

Proposed Approach	Rationale
Aspirin maintenance dose ≤100 mg/day	Higher aspirin maintenance doses increase bleeding, and there is no evidence that they improve efficacy.
PPI with a preference for agents that interfere less with CYP 2C19 (e.g., pantoprazole)	Much of the excess bleeding is from the GI tract. The use of acid-suppressive agents that interfere less with CYP 2C19 minimizes the potential for a negative interaction with clopidogrel.
For warfarin, use a target INR of 2 to 2.5	Some evidence that a restricted target INR range reduces the risk of bleeding.
Manage warfarin in a specialized anticoagulation clinic	Compared with usual care, specialist clinics achieve a higher time-in-therapeutic-range of the INR.
Minimize duration of triple therapy	The risk of bleeding is highest during the first 30 days but remains elevated with long-term treatment.
Avoid NSAIDs	NSAIDs are a common cause of upper GI bleeding.
Avoid prasugrel and ticagrelor	Prasugrel and ticagrelor cannot be recommended because they are more potent and cause more bleeding than clopidogrel.

CYP, Cytochrome P450; GI, gastrointestinal; INR, international normalized ratio; NSAID, nonsteroidal antiinflammatory drug; PPI, proton pump inhibitor.