ASPIRIN WAS THE ONLY ANTIPLATELET AGENT available from the 1970s to the 1980s. Today we now have more than five agents available. These cardioactive drugs are useful in the prevention of thrombi in coronary arteries and those arteries that supply the brain, but they are much less effective in preventing thrombi that occur in veins. Antiplatelet agents are used in virtually all patients with coronary artery disease to manage the acute and chronic phases of the disease as well as its complications.

MECHANISM OF ACTION

Coronary thrombosis is known to be the major cause of coronary artery occlusion resulting in fatal or nonfatal acute myocardial infarction. Antiplatelet agents are named this because they inhibit platelet aggregation, which plays a major role in coronary thrombosis, myocardial infarction, and cardiac death.

Platelets clump on to atherosclerotic plaques, causing occlusion of the artery, and/or embolize downstream. The occlusion of these vessels may induce fatal arrhythmias and cardiac death. In patients with unstable angina, angioscopy has confirmed the presence of platelet clumps attached to the surface of eccentric atheromatous plaques that jut into the lumen of arteries causing partial to near complete occlusion. The atheromatous plaques may become fissured or rupture exposing a ‘‘porridge/gruel’’ like substance or substances that are highly thrombogenic.

However, antiplatelet agents are not expected to prevent all forms of thrombotic events. After plaque rupture the formation of a platelet-rich
thrombus requires three essential steps:

1. Platelet adhesion: This occurs shortly after an atheromatous plaque has ruptured and the process of adhesion is mediated by the platelet glycoprotein IIb receptor through its interaction with von Willebrand factor.
2. Platelet activation: The smooth discoid platelet assumes a spiculated form, thus increasing the surface area of the platelet membrane where thrombin is generated.

3. Platelet aggregation: Platelet activation converts the glycoprotein IIb/IIIa receptor into a form that can bind fibrinogen and aggregation occurs.

INDICATIONS

Antiplatelet agents are of proven value in the management of non-ST segment elevation myocardial infarction; stable and unstable angina; post coronary artery bypass graft (CABG), coronary artery stents, cerebral transient ischemic attacks (TIAs); and lone atrial fibrillation in individuals younger than 65.

AVAILABLE ANTIPLATELET AGENTS

Currently used antiplatelet agents include aspirin, clopidogrel (ticlopidine still has a role), dipyridamole plus aspirin, and platelet glycoprotein IIb/IIIa receptor blockers.

Aspirin
Acetylsalicylic acid irreversibly acetylates the enzyme cyclooxygenase. This enzyme is necessary for the conversion of platelet arachidonic acid to thromboxane A2, a powerful platelet-aggregating agent. Cyclooxygenase is inhibited by all nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin transfers the acetyl group to the enzyme that is irreversibly inactivated. Other NSAIDs such as ibuprofen act as reversible inhibitors of cyclooxygenase.

the prevention of fatal and nonfatal heart attacks. It is important for individuals to realize that a rapid-acting aspirin formulation such as two 80- to 81-mg chewable aspirins taken soon after the onset of chest pain has been shown to cause a 25% reduction in fatal and nonfatal myocardial infarction, whereas nitroglycerin has no effect on prevention. Nitroglycerin ameliorates the pain of stable, mild angina and its use has been overvalued. A recent study by Gum et al. demonstrated the natural history of aspirin resistance and documented a greater than threefold increase in the risk of major adverse events associated with aspirin resistance. Fortunately this form of resistance is rare and occurred in less than 5% of the
326 stable cardiovascular patients administered aspirin.

Clopidogrel
Clopidogrel is a thienopyridine derivative and an anolog of ticlopidine; the drug inhibits platelet aggregation by inhibiting adenosine diphosphate (ADP) induced platelet activation and inhibits platelet fibrinogen binding. Clopidogrel is more effective than ticlopidine, but is considerably less toxic. Clopidogrel prevents platelet degranulation and the release reaction which produces prothrombotic substances. This drug selectively and irreversibly prevents ADP from binding to the platelet ADP receptor and inhibits the transformation of the glycoprotein IIb/IIIa receptor to the form that binds fibrinogen and links platelets. Clinical studies confirm the drug’s effectiveness.

CAPRIE Study
In the Clopidogrel versus Aspirin in Patients at Risk for Ischemic Events (CAPRIE) study, the control was marginally better than aspirin ( p¼0.045). Clopidogrel is recommended when aspirin is not tolerated.

CURE Trial
The Clopidogrel in Unstable Angina Recurrent Events (CURE) trial was a double-blind placebo-controlled randomized trial with clopidogrel versus placebo in addition to aspirin and other optimal therapy for patients with unstable angina and non-ST elevation acute myocardial infarction (MI). Of the 12,652 patients, 16.5% (2072) had CABG surgery and 21% (2662) had percutaneous coronary intervention (PCI). At follow up 12 months later clopidogrel treatment caused a 20% relative risk reduction in the outcome of MI, stroke, or cardiovascular death ( p¼0.00009). Significant bleeding occurred in the clopidogrel group compared with the placebo group (3.7% vs. 2.7%; p¼0.001), but there was no significant increase in life-threatening bleeding: 135 bleeds (2.2%) for clopidogrel and 112 bleeds (1.8%) for the placebo group ( p¼0.13). The major risk of bleeding with clopidogrel has been noted in patients with acute coronary syndromes scheduled for immediate CABG. In the CURE study most patients undergoing bypass surgery had the study drug stopped for a short period of time (days before surgery).

PCI CURE
The PCI CURE study was a prospectively planned substudyof CURE. The study was confined to the 2658 patients who underwent PCI and randomized to clopidogrel and aspirin versus just aspirin. At 30 days there was a significant benefit of clopidogrel over placebo. Most important, the benefit of clopidogrel appeared identical regardless of whether patients received PCI on an emergency basis or days after discharge.

CREDO Trial
This trial randomized 2116 patients. Clopidogrel 300 mg or 600 mg plus aspirin was administered from 3 to 24 h before PCI. At one year patients who received clopidogrel plus aspirin greater than 6 h before PCI caused a 26.9% reduction in the risk of death, MI, or stroke ( p¼0.02). Clopidogrel, 600-mg loading dose given 12–24 h (atleast 6 h) prior to PCI and stenting is a recommended regimen. In this regard, clopidogrel has largely replaced
ticlopidine. Because of the major risk for bleeding with glycoprotein receptor blockers, clopidogrel and aspirin combination therapy should be the preferred therapy for patients with high-risk unstable angina or non-ST elevation acute MI undergoing PCI. The combination is particularly advisable when intracoronary stents are used. Because of the major risk for bleeding with glycoprotein receptor blockers, clopidogrel and aspirin combination therapy should be the preferred therapy for patients with high-risk unstable angina or non-ST elevation acute MI except in patients undergoing urgent CABG. Intermediate- and low-risk patients not due to receive urgent PCI and in whom further tests are necessary and when PCI is deferred days to months after the acute event appear to be best treated with the clopidogrel and aspirin combination instead of platelet receptor blockers. In patients scheduled for urgent CABG, clopidogrel should be withheld to avoid bleeding.

Clopidogrel versus Ticlopidine
Because ticlopidine causes leukopenia and rarely agranulocytosis, it has been replaced by clopidogrel. A recent randomized clinical trial, however, indicates superiority of ticlopidine over clopidogrel after placement of coronary artery stents. In a study by Muller et al. in 700 patients with 899 lesions, cardiovascular death occurred in 8 patients administered ticlopidine versus 26 patients with clopidogrel ( p¼0.003). The combined end point of cardiovascular death or nonfatal MI occurred in 19 patients receiving ticlopidine versus 40 patients administered clopidogrel ( p¼0.005); after adjustment for covariables, ticlopidine reduced the risk of death by 63% compared with clopidogrel. Most important, clopidogrel will be a frequently used cardioactive agent worldwide in patients undergoing PCI. Unfortunately, clopidogrel activation requires the CYP450 3A4 system; antiplatelet activity of the drug is substantially inhibited by statins metabolized in the liver by the cytochrome pathway. These statins include the commonly used atorvastatin, simvastatin, and fluvastatin. Pravastatin and rosuvastatin are excreted by the renal system and do not interact. Inhibitory effects have not
been reported for ticlopidine. The high use of hepatic metabolized statins in this study may explain the superiority of ticlopidine over clopidogrel.

Platelet Glycoprotein IIb/IIIa Receptor
Blockers

There are approximately 75,000 glycoprotein IIb/IIIa receptors on the surface of each platelet. Antagonism of these receptors blocks the final common pathway for platelet aggregation — the binding or fibrinogen to the platelet glycoprotein receptors; platelet aggregation caused by thrombin, thromboxane A2, ADP, collagen, and shear induced platelet aggregation is prevented. Unfortunately, these agents do not affect platelet activation and degranulation, unlike ADP receptor antagonists which are active at much earlier stages of the atherothrombotic cascade.

Abciximab (ReoPro)
This widely used platelet receptor blocker inhibits both alpha IIb3 receptor and alpha v beta 3 receptors. Several randomized clinical trials have documented the beneficial effects when used for patients undergoing urgent PCI. This drug is not recommended for patients who are not scheduled for urgent PCI. Dosage would include 0.25 mg/kg IV bolus over at least 1 minute, immediately followed by IV infusion of 0.125 mgram/kg/minute for 18–24 h, concluding 1 h after PCI.

Eptifibatide (Integrilin)
This platelet receptor blocker has actions that are similar to abciximab. In a randomized clinical trial (PURSUIT), a significant benefit was observed in patients who underwent PCI within 72 h with no benefit at 30 days in those without PCI. In another large trial (TACTICS), eptifibatide was beneficial only in patients with acute coronary syndromes treated with early invasive PCI. In another trial (TARGET), the drug caused less protection from major ischemic events than abciximab. In the trial PRISMPLUS, eptifibatide reduced events at seven days but not at six months. Dosage would be IV bolus of 135 mgram/kg followed by an infusion of 0.5 mgram/kg/minute for a further 20–24 h after PCI.

Tirofiban (Aggrastat)
This platelet receptor blocker shows specificity toward alpha IIbb 3 receptor and has a shorter biological half-life than abciximab and eptifibatide. Tirofiban and eptifibatide are indicated only in patients in whom immediate PCI is not planned. In this population of patients the combination
of clopidogrel and aspirin may prove to be more efficacious at 30 days and 1 year follow up. A meta-analysis of randomized clinical trials with these three agents with the exception of abciximab used as indicated for PCI planned within 24 h indicates that nondiabetic patients had no survival benefit.

In a large randomized trial (TACTICS) patients were treated with tirofiban for 48 h plus aspirin and heparin and randomized to either invasive therapy (coronary angiography and revascularization) or conservative strategy. It is claimed that at 6 months there was a significant reduction in death or MI ( p¼0.0498; p¼0.05) This p¼0.05 is hardly the level of significance required to recommend a treatment strategy to the population at large. In clinical medicine it is essential to achieve a significance level of p <0.02 to be meaningful in terms of
saving lives.

Oral Agents
Several randomized clinical trials have shown no benefit with oral agents that included orbofiban (in the OPUS trial), sibrafiban (in SMPHONY, and xemilofiban (in the EXCITE trial) caused excess mortality, usually sudden death, and approximately a 30% increase in mortality. In five large randomized trials oral platelet receptor blockers showed a consistency toward increased mortality when compared with placebo. A 37% increase in mortality was observed in a meta-analysis of four large trials. Thirty days after commencement of one trial there was a 40% higher incidence of MI associated with these agents. Except for the proven beneficial defects of abciximab for patients undergoing primary PCI, the IV agents, also have not been a major success in terms of causing significant improvement in survival at 6 months, and they cause a significantly high excess in the incidence of major bleeding. The partial effectiveness of oral and IV agents may relate to the fact that they do not affect platelet activation and degranulation; processes that occur very early in the stage of the platelet thrombotic process. Several randomized clinical trials in progress should indicate which platelet receptor blocker is best for acute clinical situations and the role for clopidogrel combined with aspirin in patients stratified to receive PCI versus
conservative therapy.