ADP Antagonists Ticlopidine and Clopidogrel

Pharmacology

Ticlopidine and clopidogrel are thienopyridine derivatives that inhibit the binding of ADP to its receptor (Fig. 1) (55). There are, in fact, multiple ADP receptors, all of which are part of the membrane-bound nucleotide P2 receptor family. It is believed that ticlo-pidine and clopidogrel inhibit the P2TAC receptor, which is linked to adenylate cyclase inhibition (56). The thienopyridines can also indirectly inhibit the activity of several other platelet agonists such as arachidonic acid, collagen, thrombin, epinephrine, and

Fig. 2. Cumulative vascular mortality in d 0-35 in the ISIS-2 trial for all patients allocated aspirin vs all patients allocated placebo tablets. Reproduced with permission from ref. 2.

serotonin. This is thought to occur because the aggregation response to these agonists is augmented by the initial release of ADP from activated platelets. At high concentrations of these agonists, platelet aggregation is ADP-independent, and therefore, ticlopidine and clopidogrel have no significant effect. Unlike aspirin, the ADP antagonists can inhibit platelet aggregation in response to vascular shear stress (57). Observations that ticlopidine can block GP IIb/IIIa-mediated platelet aggregation (58) probably reflect a downstream effect of ADP inhibition rather than a direct effect. After starting a standard daily oral maintenance dose of either ticlopidine or clopidogrel, the full antiplatelet effect is not seen for 3-5 d and then persists for 4-8 d after drug discontinuation, consistent with an in vivo metabolite causing irreversible platelet inhibition (58-60). However, administration of an oral loading dose results in antiplatelet effect being apparent after 60-90 min (61).

Gastrointestinal (GI) upset, nausea, vomiting, diarrhea, and rashes occur in approx 10-20% of patients taking ticlopidine; many of the GI side effects can be eliminated by having the patient take ticlopidine with food. The most serious adverse effects are idiosyncratic neutropenia, which has been reported to occur in 1% of patients, and throm-botic thrombocytopenic purpura (TTP), which occurs in <0.1% of patients (62,63). Clopidogrel enjoys a better side effect profile with lower rates of GI and dermatologic adverse reactions and rates of neutropenia and TTP that are roughly comparable to what is seen in the overall population. For these reasons, it has largely supplanted ticlopidine.

Clinical Data

To date, there are few data regarding the efficacy of the ADP antagonists in ST-ele-vation myocardial infarction. However, two ongoing trials, CLARITY-TIMI 28 and COMMIT, will address this issue. The former is an angiographic study that will examine the effect of clopidogrel on late infarct-related artery patency in patients undergoing fibrinolysis. The latter is a phase III trial that will examine the effect of clopidogrel on mortality in patients undergoing fibrinolysis with a nonfibrin-selective lytic. However, while we await the results of these studies, there are several lines of evidence that support the utility of ADP antagonists as adjunctive antiplatelet therapy in acute coronary syndromes.

The ADP antagonists have become standard of care after intracoronary stent deployment to reduce thrombotic complications. The Intracoronary Stenting and Antithrom-botic Regimen (ISAR) trial demonstrated that, compared to anticoagulant therapy, combination antiplatelet therapy with aspirin and ticlopidine resulted in an 86% reduction in stent occlusion, an 82% reduction in reinfarction, a 78% reduction in reintervention, and elimination of severe hemorrhagic complications (64). In a subgroup analysis of 123 patients with stent placement for acute myocardial infarction, antiplatelet therapy resulted in a significant 84% reduction (from 21 to 3.3%, p = 0.005) in clinical events defined as cardiac events (cardiac death, reinfarction, reintervention) plus noncardiac events (noncardiac death, stroke, severe hemorrhage) (65). The Stent Anticoagulation Regimen Study (STARS) demonstrated that the incidence of adverse events (death, emergent coronary artery bypass graft [CABG], myocardial infarction, or subacute closure) was significantly lower with aspirin plus ticlopidine (0.6%) as compared to aspirin alone (3.6%,p < 0.001) or aspirin plus warfarin (2.4%,p = 0.01) (66). Several recent randomized trials suggest that, compared with ticlopidine, clopidogrel offers equivalent efficacy and better safety and tolerability (67-69).

In the Clopidogrel versus Aspirin in Patients at Risk of Ischeamic Events (CAPRIE) trial, 19,185 patients who had either a recent ischemic stroke, a myocardial infarction in the past 35 d, or symptoms of peripheral arterial disease were randomized to clopidogrel 75 mg orally once daily or aspirin 325 mg orally once daily (70). Treatment with clopidogrel resulted in a statistically significant 8.7% reduction in the combined primary endpoints of ischemic stroke, myocardial infarction, or vascular death (from 5.83 to 5.32%, p = 0.043). More recently, the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial demonstrated that in 12,562 patients presenting with unstable angina, the addition of clopidogrel to a standard regimen of aspirin and unfrac-tionated heparin resulted in a 20% reduction in the rate of the composite endpoint of death, myocardial infarction, and stroke (from 11.4 to 9.3%, p < 0.001) (71). There was a 38% increase in major bleeding, but no statistically significant increase in life-threatening bleeding.

Glycoprotein IIb/IIIa Inhibitors

Pharmacology

The glycoprotein IIb/IIIa receptor (GP IIb/IIIa) is a member of the integrin super-family of heterodimeric adhesion molecules that is found on platelets (40). It is the primary receptor for platelet aggregation through binding to fibrinogen. GP IIb/IIIa contains two domains responsible for the binding of adhesive proteins (Fig. 3) (72).

Fig. 3. GP IIb/IIIa structure. The IIIa (b3) subunit contains a domain whose ligand is the peptide sequence RGD, which is found in each a-chain of fibrinogen. The IIb (aIIb) subunit contains a domain whose ligand is the dodecapeptide HHLGGAKQAGDV, which is found in the y chain of fibrinogen. Reproduced with permission from ref. 72.

One domain is on the GP IIIa subunit and its ligand is the peptide sequence RGD. The other domain is on the GP IIb subunit and its ligand is the dodecapeptide HHLGGAKQAGDV. The dodecapeptide is found only in fibrinogen and is located on the y chain. Conversely, the RGD sequence is found in many peptides including fib-rinogen (where it is located on the a chain), fibronectin, vitronectin, vWF, and throm-bospondin. GP IIb/IIIa is unable to bind fibrinogen unless the platelet is first activated by an agonist, which then induces a conformational change in GP IIb/IIIa, revealing the binding domain and rendering the molecule a competent fibrinogen binder. Platelet aggregation occurs when two activated platelets bind to the same fibrinogen molecule (each to one end), thereby forming a fibrinogen bridge between the two platelets.

GP IIb/IIIa inhibitors are particularly attractive as antiplatelet agents, because they can block the final step in platelet aggregation triggered by all endogenous platelet activators. There are several types of GP IIb/IIIa inhibitors (40,73). In 1985, a mouse mon oclonal antibody against GP Ilb/IIIa (known as 7E3) was generated (74); subsequent clinical trials have used abciximab (ReoPro), which is a Fab fragment of a chimeric human-mouse genetic reconstruction of 7E3 (abbreviated c7E3 Fab). Based on the dis-integrins, which are natural peptides derived from snake venom that contain either an RGD-based or KGD-based sequence, researchers developed small-molecule GP IIb/IIIa inhibitors including synthetic peptide compounds, such as the cyclic KGD peptide analog eptifibatide (Integrilin) (75,76), and nonpeptide mimetics, such as tirofiban (Aggrastat) (77,78).

There are several important differences in the pharmacokinetics and pharmacodynamics of the currently available GP IIb/IIIa inhibitors. Abciximab has a very high affinity for GP IIb/IIIa and a long half-life (8-12 h), and after discontinuation of the infusion, platelet function returns gradually. In contrast, the small-molecule inhibitors eptifibatide and tirofiban have short half-lives, and platelet function returns quickly after discontinuation of the infusion. Although it has high affinity, abciximab has low specificity and binds to other integrins, including the vitronectin receptor (GP aVb3), which is found on endothelial cells. Whether this is of clinical relevance remains unknown. In contrast, eptifibatide and tirofiban are extremely specific for the GP IIb/IIIa receptor. In addition to the expected side effect of excess bleeding, abciximab has also been associated with profound thrombocytopenia in 0.5-1.0% of cases (79) and the development of anti-mouse antibodies in 5-6% of cases (80). However, in the ReoPro Readministration Registry, retreatment with abciximab was not associated with diminished efficacy or serious side effects, although the cases of thrombocytopenia tended to be more profound (81).

Clinical Data

Primary Angioplasty. All three GP IIb/IIIa inhibitors have been tested extensively in patients undergoing percutaneous coronary interventions (PCIs) and pooled analyses have demonstrated a 33% reduction in the composite of death, myocardial infarction, or the need for urgent revascularization through 30 d (73). The early trials, however, generally excluded patients undergoing intervention in the setting of an acute myocardial infarction.

More recently, though, four trials have examined the efficacy of GP IIb/IIIa inhibitors in patients undergoing primary angioplasty for acute ST-elevation myocardial infarction. In the ReoPro in Acute Myocardial Infarction and Primary PTCA Organization and Randomized Trial (RAPPORT), 483 patients were treated with abciximab or placebo before primary balloon angioplasty. Treatment with abciximab was associated with a 48% reduction in death, reinfarction, or the need for urgent revascularization by 30 d (p = 0.03) (82). However, the majority of this benefit derived from a reduction in the need for urgent revascularization. Major bleeding was twice as common in the abciximab group.

As with elective PCI, stenting has now become common in primary angioplasty for ST-elevation myocardial infarction. In the ISAR 2 trial, 401 patients undergoing intra-coronary stenting for ST-elevation myocardial infarction were randomized to abciximab or placebo (83). Treatment with abciximab was associated with a 52% reduction in the rate of death, reinfarction, or target lesion revascularization at 30 d (p = 0.038). Importantly, the magnitude of the risk reductions for each of the individual components of the composite end point were similar. Moreover, the 5% absolute reduction in the composite end point seen at 30 d persisted through 1 yr of follow-up.

Fig. 4. Kaplan-Meier curves showing the cumulative incidence of the primary end point (death, reinfarction, or urgent target-vessel revascularization) at 30 d and 6 mo in the ADMIRAL trial for patients randomized to stent plus placebo (solid squares) vs stent plus abciximab (open circles). Reproduced with permission from ref. 84.

Fig. 4. Kaplan-Meier curves showing the cumulative incidence of the primary end point (death, reinfarction, or urgent target-vessel revascularization) at 30 d and 6 mo in the ADMIRAL trial for patients randomized to stent plus placebo (solid squares) vs stent plus abciximab (open circles). Reproduced with permission from ref. 84.

Similar results were seen in the 300 patients in the Abciximab Before Direct Angioplasty and Stenting in Myocardial Infraction Regarding Acute and Long-Term Follow-up (ADMIRAL) study, in which treatment with abciximab in patients undergoing primary stenting for ST-elevation myocardial infarction had a 59% reduction in the rate of death, reinfarction, or the need for urgent target vessel revascularization by 30 d (p = 0.01) (Fig. 4) (84). Angiographic data demonstrated improved rates of TIMI flow grade 3 in the culprit artery both before and after stenting. The magnitude of the clinical benefits seen with abciximab persisted without attenuation through 6 mo (Fig. 4). Moreover, there was a lower rate of elective target vessel revascularization by 6 mo, raising the possibility that abciximab reduced the rate of restenosis.

Fig. 5. Proportion achieving TIMI flow grade 3 in the TIMI 14 trial (87) at 60 and 90 min for al patients (dose-finding and dose-confirmation) randomized to accelerated full-dose alteplase (open bars) vs reduced-dose alteplase (15 mg bolus followed by 35 mg infusion over 60 min) plus abcix-imab (solid bars).

Fig. 5. Proportion achieving TIMI flow grade 3 in the TIMI 14 trial (87) at 60 and 90 min for al patients (dose-finding and dose-confirmation) randomized to accelerated full-dose alteplase (open bars) vs reduced-dose alteplase (15 mg bolus followed by 35 mg infusion over 60 min) plus abcix-imab (solid bars).

The results from the CADILLAC study have been published (85). This was a large study in 2082 patients with acute myocardial infarction who were randomized in a 2 X 2 factorial design to balloon angioplasty vs stent and to abciximab vs placebo. Treatment with abciximab resulted in approx 15% reductions in recurrent ischemic events in both the balloon angioplasty and primary stenting arms.

Fibrinolysis. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 pilot study first examined the safety and utility of abciximab given after thrombolysis for acute myocardial infarction (86). Patients were treated with accelerated alteplase and aspirin, and were randomized to receive a bolus of abciximab at 15 h, 6 h, or 3 h after the beginning of the alteplase infusion at doses ranging from 0.1 to 0.25 mg/kg. There was no significant difference in the bleeding or thrombocytopenia rates. Although not designed to detect differences in clinical cardiac events (e.g., angina, myocardial infarction, urgent revascularization, or death), this combined end point was seen in 13% of the pooled abciximab group vs 20% of the control group.

TIMI 14 was a large angiographic trial that evaluated the efficacy of full-dose abciximab in conjunction with reduced-dose lytic (87). Ninety-minute angiography revealed that the rates of TIMI flow grade 3 were 32% in patients treated with abciximab alone, 62% in patients treated with alteplase alone, and 77% in patients receiving full-dose abciximab plus reduced-dose alteplase (15-mg bolus, followed by a 35-mg infusion over 60 min) (p = 0.01). Moreover, at 60 min, rates of TIMI flow grade 3 were 43% in the alteplase group compared to 72% in the abciximab plus reduced-dose alteplase group (p = 0.0009) (Fig. 5).

Major bleeding rates were similar in the alteplase-alone and the abciximab plus reduced-dose alteplase groups. Interestingly, in a very-low-dose heparin arm (bolus of 30 U/kg followed by an infusion at 4 U/kg/h), the rate of 60-min TIMI flow grade 3 was 68% and the major bleeding rate was only 1%. These findings suggest that future optimization of the heparin dose may minimize bleeding complications without significantly compromising efficacy.

Fig. 6. Proportion of patients with the primary end point of death (solid bars) or the composite end point of death and nonfatal reinfarction (solid and open bars) in the GUSTO V trial (91) for patients randomized to abciximab plus reduced-dose reteplase vs reteplase alone.

Abciximab was tested in conjunction with reduced doses of other fibrinolytics. In the Strategies for Patency Enhancement in the Emergency Department (SPEED) (88) and the reteplase phase of TIMI 14 (89), combination therapy consisting of full-dose abciximab and reduced-dose reteplase (5 + 5 U) resulted in marginally higher rates of TIMI flow grade 3 at 60-90 min compared to full-dose reteplase alone (54 vs 47% in SPEED and 73 vs 70% in TIMI 14, p = NS for both). In the Enoxaparin and tenecteplase (TNK-tPA) with or without GP IIb/IIIa Inhibitor as Reperfusion Strategy in ST-elevation myocardial infarction (ENTIRE) study, abciximab plus reduced dose TNK-tPA was compared to full-dose TNK-tPA (patients also were randomized to unfractionated heparin vs the low-molecular-weight heparin enoxaparin, discussed below) (90). Combination therapy resulted in similar rates of TIMI flow grade 3, but trends towards higher rates of complete ST-segment resolution by 180 min and lower rates of death or myocardial infarction among patients receiving unfractionated heparin (6.5 vs 15.9%).

The overall promising results with combination reperfusion therapy in pilot studies, coupled with prior observations from the Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries (GUSTO) I angiographic substudy that a 23% improvement in the proportion of patients achieving TIMI flow grade 3 was associated with a 1% absolute decrease in mortality (5), led to GUSTO V a phase III clinical trial in 16,588 patients comparing abciximab plus reduced-dose reteplase to reteplase alone (91). The 30-d mortality rates were not statistically different between the abciximab plus reduced-dose reteplase (5.6%) and the reteplase alone (5.9%) arms. However, patients receiving combination therapy did have a 16% lower rate of the combined end point of death or nonfatal reinfarction (p = 0.0011; Fig. 6) as well as a 12% lower rate of recurrent ischemia (p = 0.004) and trends toward lower rates of a variety of other end points including malignant arrhythmias and mechanical complications. Although rescue angioplasty was used infrequently, it did occur more often in the reteplase group (8.6 vs 5.6%, p < 0.0001), and this may have minimized potential mortality differences between the two arms. Moderate and severe bleeding was twice as frequent in the combination therapy arm (Fig. 6). Rates of intracranial hemorrhage (ICH) were similar in patients <75 yr of age, but twice as high in patients >75 yr of age.

In the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT) III trial, patients were randomized to one of three regimens: fUll-dose TNK-tPA plus unfractionated heparin, full-dose TNK-tPA plus the low-molecular-weight heparin enoxaparin, or reduced-dose TNK-tPA plus abciximab and unfractionated heparin (92). The 30-d mortality rates were not statistically significantly different between the abciximab and unfractionated heparin treatment groups (6.6 vs 6.0%, p = 0.4). However, the rate of the composite end point of death, in-hospital reinfarction, or in-hospital refractory ischemia was lower in the abciximab arm compared with the unfractionated heparin arm (11.1 vs 15.4%, p < 0.001). Major bleeding, however, was twice as high in the abciximab arm (4.4%) compared to the unfractionated heparin arm (2.2%).

Analogous to the approach with abciximab, initial studies examining the utility of eptifibatide in pharmacologic reperfusion for ST-elevation MI combined different doses of eptifibatide with a full-dose of a fibrinolytic. In IMPACT-AMI, combination therapy with the highest dose of eptifibatide and full-dose alteplase resulted in very high rates of patency (93%) and TIMI flow grade 3 (71%), but this degree of success was not replicated in the dose-confirmation phase, in which combination therapy was not superior to lytic alone (93).

In another trial, patients with acute myocardial infarction were given full-dose strep-tokinase and different doses of eptifibatide or placebo (94). Treatment with eptifibatide was associated with a higher likelihood of achieving TIMI flow grade 3 in the infarct-related artery at 90 min (50 vs 32%), but at the expense of increased bleeding complications.

In the Integrilin and Reduced Dose Thrombolytic in Acute Myocardial Infarction (INTRO-AMI) study, testing of multiple different combinations of eptifibatide and alteplase in a dose-finding phase led to two regimens being tested in a dose-confirmation phase: a "180/1.33/90" regimen (initial 180 ig/kg bolus, infusion at 1.33 ig/kg/h, and then a second 90 ig/kg bolus 30 min later) and a "180/2.0/90" regimen (with the second bolus 10 min later) (95). Combination therapy using the 180/2.0/90 regimen yielded superior rates of TIMI flow grade 3 compared to alteplase alone (56 vs 40%, p = 0.04).

The Integrilin + TNK in AMI (INTEGRITI) angiographic trial examined combinations of eptifibatide and reduced-dose TNK-tPA. A 180/2.0/180 regimen appeared most promising in the dose-finding phase. In the dose-confirmation phase, compared with patients receiving full-dose TNK-tPA alone, there were trends toward higher rates of TIMI flow grade 3 (59 vs 49%, p = 0.15) and complete ST resolution (71 vs 61%, p = 0.08) in patients receiving combination therapy (96).

In summary, combination therapy with a reduced-dose fibrinolytic and a GP IIb/IIIa inhibitor does offer improvements in infarct-related artery patency, but these have not translated into mortality benefits. It may be that, between rescue angioplasty and improved overall medical therapy (e.g., angiotensin converting enzyme [ACE] inhibitors and statins), small differences in patency do not have a large impact on survival. Nonetheless, the reductions in nonfatal ischemic events seen with combination therapy are clinically important. Moreover, combination therapy offers a more attractive transi tion to the cardiac catheterization laboratory than does full-dose fibrinolytic therapy without a GP IIb/IIIa inhibitor on board. Studies helping to define the optimal facilitated angioplasty regimen are ongoing.

Other Antiplatelet Agents Nonsteroid Anti-Inflammatory Drugs

Unlike aspirin, nonsteroid anti-inflammatory drugs (NSAIDs) are reversible COX inhibitors. Although studied in the setting of acute myocardial infarction, they have not been shown to be superior to aspirin (97). However, their antiplatelet effects have been highlighted by reports from some (98,99), but not all (100), studies in which patients not on aspirin who were assigned new selective COX-2 inhibitors had higher cardiovascular thrombotic events than did patients assigned to NSAIDs. It should be noted, though, that not all NSAIDs exert the same antiplatelet effect, and there is even some evidence that certain NSAIDs may block aspirin's antiplatelet effect (101).

Sulfinpyrazone

Sulfinpyrazone is a uricosuric agent structurally related to phenylbutazone. It is a competitive inhibitor of COX but it may inhibit platelets through other mechanisms as well. Although in one study it reduced the rate of reinfarction in patients after myocar-dial infarction (102), there are no consistent data supporting the utility of sulfinpyra-zone in acute coronary syndromes.

Dipyridamole

Dipyridamole inhibits platelets through an unknown mechanism: it may act as a phosphodiesterase inhibitor, thereby increasing concentrations of cAMP and maintaining the platelet in its resting state, it may stimulate prostacyclin synthesis, or it may inhibit cellular uptake and metabolism of adenosine (103). Clinically, dipyridamole is a weak antiplatelet agent with no established role in acute coronary syndromes (104).

Ridogrel

Ridogrel is a thromboxane synthase inhibitor as well as a competitive TXA2/ prostaglandin endoperoxide (PGEND) receptor blocker (105,106). This dual activity allows ridogrel to inhibit platelet activation several ways (Fig. 1). There has been one randomized controlled trial of ridogrel in acute myocardial infraction. In the Ridogrel vs Aspirin Patency Trial (RAPT), 907 patients presenting within 6 h of an acute myocardial infarction were treated with streptokinase 1.5 MU and randomized to re-ceive either ridogrel 300 mg IV bolus, followed by 300 mg orally 2X daily, or aspirin 250 mg IV bolus, followed by 160 mg orally once daily (107). There were no differences in the rates of infarct-related artery patency at predischarge angiography or mortality.

Prostacyclin and Analogues

Prostacyclin acts both as an antiplatelet agent and as a vasodilator. Its antiplatelet effects are mediated through stimulation of adenylate cyclase. This causes an increase in levels of cAMP, thereby stimulating cAMP-dependent protein kinases, decreasing cytoplasmic calcium levels, and maintaining the platelet in its resting state (108). Receptor down-regulation and unacceptable vasodilatation leading to hypotension have limited the clinical efficacy of current prostacyclin preparations as antiplatelet agents (109).

Thrombin Inhibitors

As thrombin is the most potent endogenous platelet activator (110-112), antithrom-bins should exert an antiplatelet effect. This has been established in experimental models (113,114), and these agents are discussed in detail below.

Glycoprotein Ib and vWF inhibitors

Analogous to the development of GP Ilb/IIIa inhibitors to block platelet aggregation, GP Ib and vWF inhibitors are being developed to block platelet adhesion (42,115,116). No clinical data are available at this time. However, there is concern that these inhibitors would significantly interfere with normal hemostasis and produce unacceptable bleeding complications, as seen clinically in GP Ib deficiency (Bernard-Soulier syndrome) and von Willebrand's disease homozygotes.

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