Interventional pharmacotherapy
Coronary artery thrombosis
Platelets are central to thrombus formation. Vessel trauma during percutaneous intervention exposes subendothelial collagen and von Willebrand factor, which activate platelet surface receptors and induce the initial steps of platelet activation. Further platelet activation ultimately results in activation of platelet glycoprotein IIb/IIIa receptor—the final common pathway for platelet aggregation.Vascular injury and membrane damage also trigger coagulation by exposure of tissue factors. The resulting thrombin formation further activates platelets and converts fibrinogen to fibrin. The final event is the binding of fibrinogen to activated glycoprotein IIb/IIIa receptors to form a platelet aggregate.
Understanding of these mechanisms has led to the development of potent anticoagulants and antiplatelet inhibitors that can be used for percutaneous coronary intervention. Since the early days of percutaneous transluminal coronary angioplasty, heparin and aspirin have remained a fundamental part of percutaneous coronary intervention treatment. Following the introduction of stents, ticlopidine and more recently clopidogrel have allowed a very low rate of stent thrombosis. More recently, glycoprotein IIb/IIIa receptor antagonists have reduced procedural complications still further and improved the protection of the distal microcirculation, especially in thrombus-containing lesions prevalent in acute coronary syndromes.
Antithrombotic therapy
Unfractionated heparin and low molecular weight heparin
Unfractionated heparin is a heterogeneous mucopolysaccharide that binds antithrombin, which greatly potentiates the inhibition of thrombin and factor Xa.An important limitation of unfractionated heparin is its unpredictable anticoagulant effect due to variable, non-specific binding to plasma proteins. Side effects include haemorrhage at the access site and heparin induced thrombocytopenia. About 10-20% of patients may develop type I thrombocytopenia, which is usually mild and self limiting. However, 0.3-3.0% of patients exposed to heparin for longer than five days develop the more serious immune mediated, type II thrombocytopenia, which paradoxically promotes thrombosis by platelet activation.
Despite these disadvantages, unfractionated heparin is cheap, relatively reliable, and reversible, with a brief duration of anticoagulant effect that can be rapidly reversed by protamine. It remains the antithrombotic treatment of choice during percutaneous coronary intervention.
For patients already taking a low molecular weight heparin who require urgent revascularisation, a switch to unfractionated heparin is generally recommended. Low molecular weight heparin is longer acting and only partially reversible with protamine. The use of low molecular weight heparin during percutaneous intervention is undergoing evaluation.
Direct thrombin inhibitors
These include hirudin, bivalirudin, lepirudin, and argatroban. They directly bind thrombin and act independently of antithrombin III. They bind less to plasma proteins and have a more predictable dose response than unfractionated heparin. At present, these drugs are used in patients with immune mediated heparin induced thrombocytopenia, but their potential for routine use during percutaneous intervention is being evaluated, in particular bivalirudin.Adjunctive pharmacology during percutaneous coronary intervention
Aspirin—For all clinical settings.
Clopidogrel—For stenting; unstable angina or non-ST segment elevation myocardial infarction
Unfractionated heparin——For all clinical settings
Glycoprotein IIb/IIIa receptor inhibitors
Abciximab—For elective percutaneous intervention for chronic stable angina; unstable angina or non-ST segment elevation myocardial infarction (before and during percutaneous intervention); ST segment elevation myocardial infarction (before and during primary percutaneous intervention)
Eptifibatide—For elective percutaneous intervention for chronic stable angina; unstable angina or non-ST segment elevation myocardial infarction (before and during percutaneous intervention)
Tirofiban—For unstable angina or non-ST segment elevation myocardial infarction (before and during percutaneous intervention)
Comparison of unfractionated heparin and low molecular weight heparin
Unfractionated heparin
Molecular weight—3000-30 000 Da
Mechanism of action—Binds antithrombin and inactivates factor Xa and thrombin equally (1:1)
Pharmacokinetics—Variable binding to plasma proteins, endothelial cells, and macrophages, giving unpredictable anticoagulant effects Short half life Reversible with protamine
Laboratory monitoring—Activated clotting time
Cost—Inexpensive
Low molecular weight heparin
Molecular weight—4000-6000 Da
Mechanism of action—Binds antithrombin and inactivates factor Xa more than thrombin(2-4:1)
Pharmacokinetics—Minimal plasma protein binding and no binding to endothelial cells and macrophages, giving predictable anticoagulant effects. Longer half life. Partially reversible with protamine
Laboratory monitoringNot required
Cost—10-20 times more expensive than unfractionated heparin
Antiplatelet drugs
Aspirin
Aspirin irreversibly inhibits cyclo-oxygenase, preventing the synthesis of prothrombotic thromboxane-A2 during platelet activation. Aspirin given before percutaneous intervention reduces the risk of abrupt arterial closure by 50-75%. It is well tolerated, with a low incidence of serious adverse effects. The standard dose results in full effect within hours, and in patients with established coronary artery disease it is given indefinitely. However, aspirin is only a mild antiplatelet agent and has no apparent effect in 10% of patients. These drawbacks have led to the development of another class of antiplatelet drugs, the thienopyridines.Thienopyridines
Ticlopidine and clopidogrel irreversibly inhibit binding of adenosine diphosphate (ADP) during platelet activation. The combination of aspirin plus clopidogrel or ticlopidine has become standard antiplatelet treatment during stenting in order to prevent thrombosis within the stent. As clopidogrel has fewer serious side effects, a more rapid onset, and longer duration of action, it has largely replaced ticlopidine. The loading dose is 300 mg at the time of stenting or 75 mg daily for three days beforehand. It is continued for about four weeks, until new endothelium covers the inside of the stent. However, the recent CREDO study supports the much longer term (1 year) use of clopidogrel and aspirin after percutaneous coronary intervention, having found a significant (27%) reduction in combined risk of death, myocardial infarction, or stroke.Glycoprotein IIb/IIIa receptor inhibitors
These are potent inhibitors of platelet aggregation. The three drugs in clinical use are abciximab, eptifibatide, and tirofiban. In combination with aspirin, clopidogrel (if a stent is to be deployed), and unfractionated heparin, they further decrease ischaemic complications in percutaneous coronary procedures.Glycoprotein IIb/IIIa receptor inhibition may be beneficial in elective percutaneous intervention for chronic stable angina; for unstable angina or non-ST segment elevation myocardial infarction, for acute myocardial infarction with ST segment elevation.
Glycoprotein IIb/IIIa inhibitors currently in use
| Abciximab | Eptifibatide | Tirofiban | |
| Source | Chimeric monoclonal mouse antibody | Peptide | Non-peptide |
| Time for platelet inhibition to return to normal (hours) | 24-48 | 4-6 | 4-8 |
| Approximate cost per percutaneous coronary intervention | $1031, ˆ1023,£657 (12 hour infusion) | $263, ˆ260,£167(18 hour infusion) | $404, ˆ401,£257(18 hour infusion) |
| Severe thrombocytopenia | 1.0% (higher if readministered) | Similar to placebo | Similar to placebo |
| Reversible with platelet transfusion? | Yes | No | No |
Elective percutaneous intervention for chronic stable angina
Large trials have established the benefit of abciximab and eptifibatide during stenting for elective and urgent percutaneous procedures. As well as reducing risk of myocardial infarction during the procedure and the need for urgent repeat percutaneous intervention by 35-50%, these drugs seem to reduce mortality at one year (from 2.4% to 1% in EPISTENT and from 2% to 1.4% in ESPRIT). In diabetic patients undergoing stenting, the risk of complications was reduced to that of non-diabetic patients.
Although most trials showing the benefits of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention relate to abciximab, many operators use the less expensive eptifibatide and tirofiban. However, abciximab seems to be superior to tirofiban, with lower 30 day mortality and rates of non-fatal myocardial infarction and urgent repeat percutaneous coronary intervention or coronary artery bypass graft surgery in a wide variety of circumstances (TARGET study). In the ESPRIT trial eptifibatide was primarily beneficial in stenting for elective percutaneous intervention, significantly reducing the combined end point of death, myocardial infarction, and urgent repeat percutaneous procedure or bypass surgery at 48 hours from 9.4% to 6.0%. These benefits were maintained at follow up.
As complication rates are already low during elective percutaneous intervention and glycoprotein IIb/IIIa inhibitors are expensive, many interventionists reserve these drugs for higher risk lesions or when complications occur. However, this may be misguided; ESPRIT showed that eptifibatide started at the time of percutaneous intervention was superior to a glycoprotein IIb/IIIa inhibitor started only when complications occurred.
Unstable angina and non-ST segment elevation myocardial infarction
The current role of glycoprotein IIb/IIIa inhibitors has been defined by results from several randomised trials. In one group of studies 29 885 patients (largely treated without percutaneous intervention) were randomised to receive a glycoprotein IIb/IIIa inhibitor or placebo. The end point of “30 day death or non-fatal myocardial infarction” showed an overall significant benefit of the glycoprotein IIb/IIIa inhibitor over placebo. Surprisingly, the largest trial (GUSTO IV ACS) showed no benefit with abciximab, which may be partly due to inclusion of lower risk patients. The use of glycoprotein IIb/IIIa inhibitors in all patients with unstable angina and non-ST segment elevation myocardial infarction remains debatable, although the consistent benefit seen with these drugs has led to the recommendation that they be given to high risk patients scheduled for percutaneous coronary intervention.
Another study (CURE) showed that the use of clopidogrel rather than a glycoprotein IIb/IIIa inhibitor significantly reduced the combined end point of cardiovascular death, non{fatal myocardial infarction, or stroke (from 11.4% to 9.3%). Similar benefits were seen in the subset of patients who underwent percutaneous coronary intervention. The impact this study will have on the use of glycoprotein IIb/IIIa inhibitors in this clinical situation remains unclear.
In another group of studies (n=16 770), patients were given a glycoprotein IIb/IIIa inhibitor or placebo immediately before or during planned percutaneous intervention. All showed unequivocal benefit with the active drug. Despite their efficacy, however, some interventionists are reluctant to use glycoprotein IIb/IIIa inhibitors in all patients because of their high costs and reserve their use for high risk lesions or when complications occur.
Acute ST segment elevation myocardial infarction
In many centres primary percutaneous intervention is the preferred method of revascularisation for acute myocardial infarction. To date, randomised studies have shown that abciximab is the only drug to demonstrate benefit in this setting. The development of low cost alternatives and the potential for combination with other inhibitors of the coagulation cascade may increase the use of glycoprotein IIb/IIIa inhibitors.
Restenosis
Although coronary stents reduce restenosis rates compared with balloon angioplasty alone, restenosis within stents remains a problem. Nearly all systemic drugs aimed at reducing restenosis have failed, and drug eluting (coated) stents may ultimately provide the solution to this problem.The future
Improvements in adjunctive pharmacotherapy, in combination with changes in device technology, will allow percutaneous coronary intervention to be performed with increased likelihood of acute and long term success and with lower procedural risks in a wider variety of clinical situations. Further refinements in antiplatelet treatment may soon occur with rapidly available bedside assays of platelet aggregation.Names of trials
- CAPTURE—C7E3 antiplatelet therapy in unstable refractory angina
- CREDO—Clopidogrel for the reduction of events during observation
- CURE—Clopidogrel in unstable angina to prevent recurrent events
- EPIC—Evaluation of C7E3 for prevention of ischemic complications
- EPILOG—Evaluation in PTCA to improve long-term outcome with abciximab glycoprotein IIb/IIIa blockade
- EPISTENT—Evaluation of IIb/IIIa platelet inhibitor for stenting
- ESPRIT—Enhanced suppression of the platelet glycoprotein IIb/IIIa receptor using integrilin therapy
- GUSTO IV-ACS—Global use of strategies to open occluded arteries IV in acute coronary syndrome
- IMPACT II—Integrilin to minimize platelet aggregation and coronary thrombosis
- PARAGON—Platelet IIb/IIIa antagonism for the reduction of acute coronary syndrome events in the global organization network
- PRISM—Platelet receptor inhibition in ischemic syndrome management
- PRISM-PLUS—Platelet receptor inhibition in ischemic syndrome management in patients limited by unstable signs and symptoms
- PURSUIT—Platelet glycoprotein IIb/IIIa in unstable angina:receptor suppression using integrilin therapy
- RESTORE—Randomized efficacy study of tirofiban for outcomes and restenosis.percutaneous intervention
Percutaneous coronary intervention (PCI), commonly known as coronary angioplasty or simply angioplasty, is a therapeutic procedure to treat the stenotic (narrowed) coronary arteries of the heart found in coronary heart disease. These stenotic segments are due to the build up of cholesterol-laden plaques that form due to atherosclerosis. PCI is usually performed by an interventional cardiologist.