With Antithrombotic And Antiplatelet Drugs

Reperfusion Therapy for STEMI

The pathophysiologic substrate for STEMI is complete thrombotic occlusion of an epicardial coronary artery. As a result, management centers on immediate restoration of epicardial blood flow (Fig. 2). Either fibrinolytic therapy or primary PCI are acceptable reperfusion options for patients presenting within 12 h of symptom onset with ST elevation or new left bundle branch block (LBBB) on the presenting electrocardiogram (ECG). Owing to concerns about suboptimal efficacy and increased risk for intracranial hemorrhage in elderly patients (22,23), primary PCI is preferred in this population. Fibrinolytic therapy is not recommended routinely for patients presenting between 12 and 24 h after the onset of symptoms or for those who have a blood pressure above 180/110, and is contraindicated for patients presenting >24 hours after the onset of symptoms, and in those with only ST depression on the presenting ECG, unless a true posterior MI is suspected.

Primary percutaneous coronary intervention is considered an alternative to fibrino-lytic therapy for patients with ST elevation or presumed new LBBB, if the following criteria are met: anticipated door-to-balloon time of 90 min or less; high-volume operators; and a collaborative environment that includes experienced support staff and close integration between the emergency room and the cardiac catheterization laboratory. Primary PCI is the treatment of choice for patients presenting with cardiogenic shock, provided they are <75 yr old, and can be treated within 18 h of the onset of shock and within 36 h of the onset of symptoms (24). An algorithm for the management of STEMI is shown in Fig. 2.

Fibrinolytic Therapy for Non-ST Elevation ACS

In the TIMI IIIB study (25), 1473 patients with unstable angina or non-Q MI were randomized to tissue plasminogen activator (tPA) or placebo, in addition to unfractionated heparin (UFH) and aspirin. It was found that fibrinolytic therapy did not lead to an improvement in clinical end points, but was associated with an increase in fatal and nonfatal MI at 6 wk and 1 yr (7.5% vs 4.9%, p = 0.04). Cerebral hemorrhage occurred in four patients with tPA and in no control patients (p = 0.06). As a result of this and other trials, fibrinolytic therapy is contraindicated for patients without ST elevation or new LBBB on the presenting ECG.

Aspirin and Dipyridamole

Aspirin irreversibly inhibits cyclooxygenase I, preventing platelet synthesis of thromboxane A2, a potent vasoconstrictor and stimulator of platelet aggregation. It is indicated for all patients with ST elevation and non-ST elevation ACSs and it reduces the rate of death or MI by about 50% (26). Despite clear evidence of benefit in all patient subgroups with acute coronary syndromes, aspirin is frequently underutilized. In the Global Unstable Angina Registry and Treatment Evaluation Study (GUARANTEE) Registry (27) of unstable angina patients, only 82% of patients received aspirin. In subjects without known cardiac disease enrolled in the Physicians' Health Study (28), the benefits of aspirin were shown, particularly in those with higher serum concentrations of CRP. In this setting, CRP may be serving predominantly as a marker of those at the highest risk for adverse events. However, part of the benefit of aspirin could relate to its antiinflammatory properties, which could reduce plaque rupture and its sequelae. In patients with unstable angina, dipyridamole does not confer benefit when added to aspirin (29).

Thienopyridines: Ticlopidine and Clopidogrel

Ticlopidine is an ADP-receptor antagonist that has been shown to be useful in patients intolerant to aspirin (30). However, this agent is associated with frequent side effects, and, more important, is also associated with an increased risk for neutropenia and throm-botic thrombocytopenic purpura. Clopidogrel is another ADP-receptor antagonist that has replaced ticlopidine in clinical practice owing to a more favorable side effect profile and the fact that it is not associated with neutropenia. At steady state, this drug inhibits platelet aggregation by 40-60%. In patients with recent MI, stroke, or peripheral arterial disease, clopidogrel and aspirin appear to provide similar long-term secondary prevention benefits (31). Thus, clopidogrel is indicated as secondary prevention for patients who have either allergy or intolerance to aspirin. In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, the combination of clopidogrel and aspirin was compared with aspirin alone in a population of patients with ACS (32). Compared with aspirin alone, the combination of clopidogrel and aspirin led to a 20% relative reduction in the composite end point of cardiovascular death, MI, and stroke from 11.5% to 9.3% at a mean of 9 mo follow-up (RR: 0.80, CI: 0.72-0.89, p < 0.00005). The benefit was driven by a reduction in MI (6.7% to 5.2%; RR: 0.77, CI: 0.68-0.89, p < 0.001), but there were also trends to reduction in cardiovascular death (5.5% to 5.1%; RR: 0.92, CI: 0.791.07) and stroke (1.4% to 1.2%). Reduction in events began within 2 h of the administration of the 300-mg loading dose. These benefits were achieved at the cost of an increase in major bleeding events (2.7% to 3.6%, RR: 1.34,p < 0.003) and transfusions (2.2% to 2.8%, RR: 1.28, p < 0.03).

Unfractionated Heparin

Heparin binds with antithrombin, enhancing its ability to inactivate factor Xa and thrombin. Clinical data to support the use of UFH in addition to aspirin for patients with non-ST elevation ACS are surprisingly limited. A meta-analysis of six randomized short-term trials assessed the value of adding UFH to aspirin for the treatment of unstable angina in 1353 patients (33). There was a trend toward reduced mortality and MI (RR: 0.67; 95% CI: 0.44-1.02, p = 0.06) in the patients receiving heparin. However, only four studies reported results to 12 wk, when much of the trend in benefit was attenuated (RR: 0.82, 95% CI: 0.56-1.20, p = 0.76).

Although it has not been definitively established that the combination of heparin and aspirin is superior to either aspirin or heparin alone, guidelines usually recommend their combined use in patients with unstable angina or NSTEMI. Rebound ischemia on cessation of treatment may occur, particularly in those patients not taking aspirin. The target activated partial thromboplastin time (aPTT) is recommended to be in the range of 45-60 s on the basis of evidence from randomized trials (34). Control may be facilitated by the use of bedside monitoring and dosing indexed to patient weight.

A number of factors may contribute to limited efficacy of UFH. These include the need for antithrombin for its action, and reduced effectiveness of the heparin-antithrombin complex in the presence of fibrin monomers. The release of platelet factor 4 in response to heparin may also contribute to reactivating acute ischemia. Other limitations of UFH are the need for continuous infusions and difficulty in achieving target activated partial throm-boplastin times, because of wide variation in antithrombotic response. Heparin-induced thrombocytopenia occurs in 1-3% of patients (35).

Low-Molecular-Weight Heparins

Low-molecular-weight heparins (LMWHs) are derived from UFH by depolymeriza-tion. They have a number of practical advantages, including greater activity against factor Xa than thrombin, and greater bioavailability than UFH because of lower binding to plasma proteins and endothelial cells. This leads to a more predictable antithrombotic dose-response relationship, and eliminates the need for routine laboratory monitoring of the anticoagulant effect. The long half-life of about 4 h after subcutaneous injections enables once or twice daily subcutaneous injection. LMWHs have an increase in minor (cutaneous) bleeding compared to UFH, but have the distinct advantages of not requiring aPTT monitoring, have a reduced rate of heparin-induced thrombocytopenia (35), and intravenous site infections are avoided. Because of the long half-life of LMWH, and difficulties in achieving rapid reversal of effect, UFH is often preferred in those patients in whom early or immediate intervention is planned, and in patients with marked obesity or renal failure. However, administration of protamine sulfate results in approx 60% reversal of the anti-factor Xa effects of LMWH and may result in decreased bleeding (36,37).

The only clinical trial of a LMWH (dalteparin) compared with placebo in patients on aspirin (Fragmin in Unstable Coronary Artery Disease [FRISC]) (38) showed a benefit in death and MI (1.8% vs 4.8%) at 6 d, which persisted at 40 d. In this study, patients were required to have an unstable coronary syndrome and transient or persistent ECG changes (ST depression of 0.1 mV or more, or T-wave inversion of 0.1 mV in two adjacent leads). In FRISC, a positive troponin T (>0.1 ng/mL) differentiated between those patients who responded to dalteparin (48% lower incidence of death or MI at 40 d) from nonresponders (39) (Fig. 3). Similarly, in the Thrombolysis in Myocardial Infarction (TIMI) 11B study troponin I predicted response to enoxaparin (40) (Fig. 3).

Several major clinical studies of LMWHs have examined their efficacy compared with intravenous unfractionated heparin. Both the FRISC study (41) (dalteparin) and the Fraxiparine in Ischemic Syndrome (FRAXIS) study (42) (nadroparin) demonstrated equivalence but no advantage over UFH. Two studies of enoxaparin (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events [ESSENCE] [43] and TIMI 11B [44]) demonstrated superiority over UFH with reduction in the composite end point of death, infarction, recurrent angina, or revascularization. A prospectively planned metaanalysis of the two trials of enoxaparin (ESSENCE and TIMI 11B [45]) demonstrated superiority with a 20% reduction in the combination of death and MI when compared with UFH (p = 0.05) at 8, 14, and 43 d. Benefit has been confirmed to persist at 1 yr (46). Economic analyses of data from ESSENCE show cost savings both at 30 d (47) and 1 yr (48) in patients treated with enoxaparin.

The LMWHs differ in their ratio of anti-Xa/anti-IIa activity, with enoxaparin having relatively greater anti-Xa activity (3.5:1) than dalteparin (2.5:1) (49). The LMWHs also vary in their pharmacologic effects (50,51), including their rates of clearance, the amount of nonspecific binding, duration of effect, and effects on von Willebrand factor. In the absence of direct comparisons in clinical trials the relative effectiveness of the different LMWHs is uncertain. The current evidence, however, demonstrates the clinical benefit of enoxaparin over UFH, which is not proven with dalteparin or nadroparin.

It was hoped that the LMWHs might be particularly effective for prolonged therapy in patients at high risk for recurrent ischemic events. However, this has not been substantiated with a 3-mo study of twice daily dalteparin, compared with placebo (FRISC II) showing a reduction in the composite end point of death and MI at 1 mo, which was not sustained at 6-mo follow-up (52). Another study (TIMI 11B) of prolonged enoxaparin for 35 d after initial stabilization demonstrated no incremental benefit for prolonged therapy, with an increased risk of major bleeding (44).

6m - Death/MI/rehosp ACS

Fig. 3. Benefits of therapy in troponin-positive patients. (A) Efficacy of LMW heparins: daltep-arin (36,49) and enoxaparin (37) in troponin-positive patients. (B) Efficacy of GP IIb/IIIa receptor blockers: abciximab (71), tirofiban (82), and lamifiban (83) in troponin-positive patients. (C) Efficacy of an invasive strategy (66,67) in troponin-positive patients. In each of these studies there was no significant benefit of these treatments in troponin-negative patients.

6m - Death/MI/rehosp ACS

Fig. 3. Benefits of therapy in troponin-positive patients. (A) Efficacy of LMW heparins: daltep-arin (36,49) and enoxaparin (37) in troponin-positive patients. (B) Efficacy of GP IIb/IIIa receptor blockers: abciximab (71), tirofiban (82), and lamifiban (83) in troponin-positive patients. (C) Efficacy of an invasive strategy (66,67) in troponin-positive patients. In each of these studies there was no significant benefit of these treatments in troponin-negative patients.

Direct Antithrombins

Hirudin, hirulog, inogatran, and argatroban are selective antithrombin agents that have been subjected to clinical trials. They differ from heparin in that they do not require interaction with an intermediate enzyme and bind directly to the catalytic site of thrombin. Their proposed benefits over heparin include the ability to inactivate clot-bound thrombin, and reduction in thrombin-induced platelet activation, factor V and VIII activation, and endothelin release. The direct antithrombins are not inhibited by platelet factor 4, remain active in platelet-rich environments, and are not associated with thrombocytopenia.

Despite these theoretical advantages, large-scale trials of direct antithrombins have been disappointing. Only a small incremental benefit has been shown over standard UFH in large-scale studies. A meta-analysis (53) of the hirudin trials from the Organization to Assess Strategies for Ischemic Syndromes (OASIS) pilot, OASIS-2, and GUSTO-IIb of non-ST elevation ACS patients demonstrated a trend to risk reduction at 35 d (RR: 0.90, p = 0.06). Hirudin was associated with a higher rate of bleeding requiring transfusion than heparin. Similarly, a study of inogatran (54) showed no improvement in ischemic end points despite a clear dose-related improvement in activated partial thromboplastin time.

Early benefit at 7 d (53,55) may be attenuated by 30 d because of rebound activation of the coagulation system after termination of treatment (54,56). Owing to low event rates in these large trials, it has been difficult to demonstrate significant differences in outcomes, and apparent gains appear to be small. In addition, these agents are associated with an increase in major bleeding and are more expensive than heparin.

Warfarin

Warfarin antagonizes carboxylation of glutamate residues on vitamin K-dependent proteins, thereby inhibiting the biologic activity of coagulation factors II, VII, IX, and X. Warfarin monotherapy appears to be at least as effective as aspirin for secondary prevention in patients following MI (57). Owing to its improved safety profile and ease of use, however, aspirin is preferred for all patients except those with MI complicated by atrial fibrillation or severe left ventricular dysfunction (particularly following large anterior MI), as in these circumstances the risk for systemic embolization is markedly increased. Studies have also evaluated the combination of warfarin and aspirin post-MI. Neither fixed-dose warfarin nor low-dose warfarin titrated to an INR of approx 1.5-2.5 appears to be superior to monotherapy with either agent alone, and the combination is associated with excess bleeding risk (58-61). Thus, although warfarin is a suitable alternative to aspirin following MI in selected patients, there is currently no evidence to support a combination regimen of warfarin plus aspirin.

GP Ilb/IIIa Inhibitors

By blocking the final common pathway of platelet aggregation, GP IIb/IIIa antagonists potently inhibit platelet aggregation in response to all types of stimuli. The first GP IIb/IIIa antagonist to reach clinical practice was abciximab, a murine monoclonal Fab antibody fragment. Subsequently, both peptide (eptifibatide) and nonpeptide small molecules (tirofiban, lamifiban, sibrafiban, xemilofiban, and orbofiban) have been assessed in clinical trials. At their recommended doses, all three of the currently approved agents (abciximab, eptifibatide, and tirofiban) inhibit platelet aggregation by >80%.

In the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study (62), the combination of aspirin, heparin, and tirofiban, compared with aspirin and heparin alone, reduced the composite end point of death, nonfatal infarction, and refractory ischemia at 7 d (12.9% vs 17.9%, p = 0.004), 30 d (18.5% vs 22.3%, p = 0.03), and 6 mo (27.7% vs 32.1%, p = 0.02). Death and nonfatal infarction were reduced at 7 d (4.9% vs 8.3%, p = 0.006) and 30 d (8.7% vs 11.9%, p = 0.03), but not at 6 mo (12.3% vs 15.3%, p = 0.06). The combination of aspirin, heparin, and eptifibatide (63) similarly reduced the combination of death and MI from 15.7% to 14.2% (p = 0.042) at 30 d when compared to heparin and aspirin alone.

In the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study (64) comparing tirofiban with heparin, 13% of patients who were troponin I positive had a cardiac event (death, MI) at 30 d, compared with 4.9% in troponin-negative patients (p < 0.0001). At 30 d, in cTnI-positive patients, tirofiban lowered the risk of death (adjusted RR: 0.25, 95% CI: 0.09-0.68, p = 0.004) and MI (RR: 0.37, CI: 0.16-0.84, p = 0.01) (Fig. 3). This benefit was seen in medically managed patients (RR: 0.30, CI: 0.10-0.84, p = 0.004) and in those undergoing revascularization (RR: 0.37, CI: 0.15-0.93, p = 0.02) after 48 h of infusion treatment. In contrast, no treatment effect was seen for cTnI-neg-ative patients.

In the GUSTO IV-ACS study (65), patients with non-ST elevation ACS were randomized to an abciximab bolus with a 24- or 48-h infusion, or to placebo. All patients received aspirin and either UFH or dalteparin. Patients were required to have chest pain lasting at least 5 min in the previous 24 h, with either 0.5-mm ST depression or positive cardiac troponin, but were excluded if revascularization was planned within 30 d. The trial enrolled 7800 patients and the primary end point (death or MI at 30 d) was reached in 8.0%, 8.2%, and 9.1% of the placebo, 24-h infusion, and 48-h infusion groups, respectively (p = NS). There was no improvement in outcome in the troponin-positive or ST depression groups. Minor and major bleeding was increased, particularly in the 48-h infusion group.

The benefits of the small molecule GP IIb/IIIa inhibitors, tirofiban (62) and eptifibatide (63), have been consistent in patients with ACSs: early reductions in death, MI, and refractory ischemia have been observed, but there has been some attenuation of benefit at 6 mo. The combination of GP IIb/IIIa receptor antagonists together with LMWHs has not yet been evaluated in large clinical trials, although large studies are currently underway. A small study (66) of tirofiban in combination with enoxaparin demonstrated more consistent inhibition of platelet aggregation than when combined with UFH. As yet, there are no head-to-head studies of GP IIb/IIIa inhibitors compared with LMWHs.

Some GP IIb/IIIa inhibitors may have other clinically important effects on long-term inflammation and hyperplasia. Abciximab binds the leukocyte Mac-1 receptor (67), which may have long-term benefits in reducing inflammation, and also blocks the vitronectin receptor (68), which integrin is involved in tissue proliferation. Despite hopes that oral GP IIb/IIIa inhibitors could provide prolonged receptor inhibition and prevent recurrent ischemic events, all studies to date have been disappointing and these agents have no role in contemporary practice (Table 3).

Antiischemic Therapy

P-Blockers exert their beneficial effect in ACS by decreasing myocardial contractility and heart rate, improving the balance between oxygen supply and demand. In patients

Table 3

Summary of Evidence for Antithrombotic and Antiplatelet Drugs in the ACS

• Aspirin reduces progression to MI and cardiac mortality by about 40%.

• When used with aspirin, clopidogrel leads to a significant reduction in the composite of cardiovascular death, MI, and stroke, and in particular reduces MI by 23%, but at a cost of increased major bleeds.

• Dipyridamole does not confer any additional reduction in coronary events when added to aspirin.

• UFH, when used with aspirin, only marginally reduces death and MI when compared with placebo.

• Dalteparin reduces death and MI when compared with placebo.

• Enoxaparin is superior to UFH in reducing death and MI, whereas dalteparin and nadroparin are not.

• Prolonged use of LMWHs shows no additional benefit over short-term use.

• Direct antithrombins appear to have a marginal advantage and have the risk of increased bleeding.

• Intravenous thrombolytic therapy is ineffective and may be harmful.

• Warfarin has minimal benefits over aspirin.

• In the ACS the intravenous administration of GP IIb/IIIa inhibitors (tirofiban and eptifibatide, but not abciximab) in combination with aspirin and UFH reduce death and MI in the first months after treatment, but with attenuation of effect at 6 mo.

• The benefits of GP IIb/IIIa inhibitors are additive to the use of revascularization.

with STEMI, P-blockers reduce infarct size and prevent short-term mortality. The reduction in early mortality is largely due to prevention of sudden cardiac death, which is caused predominantly by early ventricular arrhythmias and ventricular rupture (69). In patients with normal left ventricle (LV) function, the primary benefit of long-term therapy with P-blockers is the prevention of recurrent infarction (69), whereas in patients with LV dysfunction, long-term P-blocker therapy markedly reduces mortality (70). In recent guidelines, the recommendations for P-blocker use have broadened to reflect a growing appreciation for the role of these agents in patients with LV dysfunction and mild-to-moderate congestive heart failure (CHF). Currently, early (intravenous followed by oral) P-blockers are recommended for all patients with ACS, unless moderate to severe heart failure, significant bradycardia, or severe bronchospasm is present. Long-term secondary prevention with P-blockers is indicated for most patients discharged with ACS.

Because they favorably affect both myocardial oxygen supply and demand, nitrates are of particular value in the early management of ACS. Current guidelines recommend that sublingual followed by intravenous nitroglycerin be given to patients for the immediate relief of ischemia and CHF symptoms. Clinical trial evidence does not support routine administration of nitrates after the first 24-48 h in patients without ongoing ische-mic symptoms. Although effective at relieving symptoms, nitrates have not been shown to lower mortality.

The indications for angiotensin-converting-enzyme (ACE) inhibitors in patients with ACS have expanded rapidly in recent years. Previous guidelines focused on the role of ACE inhibitors following STEMI to prevent adverse ventricular remodeling, CHF, and death. With the publication of the Heart Outcomes Prevention Evaluation Study (71), it is now clear that this class of agents also prevents ischemic complications in patients with established vascular disease and in patients at high risk for vascular disease. As a result, ACE inhibitors are now indicated for most patients with ACS who do not have hypotension (systolic blood pressure < 100) after initial treatment with P-blockers.

While recommendations for the use of P-blockers and ACE inhibitors have been extended in recent guidelines, the role of calcium channel blockers continues to diminish. In contrast to evidence for P-blockers and ACE inhibitors, clinical trials do not suggest that calcium channel blockers lower mortality. No clear indication exists for calcium channel antagonists in STEMI, and in non-ST elevation ACS, diltiazem or verapamil is recommended only in patients who meet the following criteria: (1) contraindication to P-blocker or ACE inhibitors, (2) persistent or frequently recurring ischemia, (3) absence of severe LV dysfunction, and (4) presence of refractory hypertension or tachycardia. It is also recommended that short-acting dihydropyridine calcium channel blockers be avoided altogether.

Lipid-Lowering Therapy

Long-term therapy with lipid-lowering agents (statins) is currently recommended for patients with ACS provided the concentration of LDL is > 100 mg/dL, based on results from a number of landmark secondary prevention trials (72-74). Recently, several lines of clinical evidence have converged to suggest that initiation of statin therapy should be advanced from the discharge phase to the hospital phase in patients with ACS. First, patients initiated on statins in the hospital are much more likely to remain on therapy at long-term follow-up (75). Second, in-hospital initiation of high-dose statins reduces recurrent ischemic events when compared with traditional strategies in which statins are initiated after several months of dietary intervention (76). A variety of mechanisms likely explain the benefits of statins in the early phase following ACS, including low-density-lipoprotein (LDL) reduction, improved endothelial function, reduced inflammation, and inhibition of thrombin generation.

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