Recent advances in antiplatelet therapy
Jeffrey Lefkovits, Department of Cardiology, Royal Melbourne Hospital, Melbourne

Summary

Aspirin is a highly successful antiplatelet drug; however, increased understanding of platelet biology has led to the development of new antiplatelet drugs that are potentially more effective. The platelet glycoprotein IIb/IIIa receptor antagonists block the platelet receptor for fibrinogen which is responsible for platelet aggregation. These drugs are more efficacious than aspirin in reducing ischaemic complications following coronary angioplasty. Ticlopidine also interferes with the glycoprotein IIb/IIIa receptor and is more effective than aspirin for secondary stroke prevention. Ridogrel inhibits the arachidonic acid pathway at two key sites, and may prove to be an effective adjunct to thrombolysis for myocardial infarction. Further evaluation with these new antiplatelet drugs is ongoing.

Key words: platelet glycoprotein IIb/IIIa receptor antagonists, ticlopidine, arachidonic acid pathway inhibitors

Aust Prescr 1996;19:98-101

Introduction: the 'older' antiplatelet drugs
The past decade has witnessed an evolution in the understanding of the role of platelets in cardiovascular disease. Platelets have been implicated in the formation of rapidly progressing atherosclerotic lesions, and play a key role in acute arterial thrombosis. The importance of platelets is highlighted by the unrivalled therapeutic success of the antiplatelet drug, aspirin. This drug, available for over a century, has been shown in hundreds of trials to reduce the risk of serious ischaemic events in several cardiovascular disease states including stroke, myocardial infarction, unstable angina and following coronary artery bypass surgery. Although aspirin has been the mainstay of antiplatelet therapy for several decades, it is acknowledged as a relatively weak inhibitor of platelet activity. Aspirin inhibits cyclo-oxygenase, irreversibly blocking the conversion of arachidonic acid to thromboxane A2 (TXA2) - a potent stimulus of platelet aggregation. However, there are more than 90 other metabolic pathways leading to platelet aggregation that are independent of arachidonic acid and therefore not inhibited by aspirin.

Sulfinpyrazone and dipyridamole are alternative antiplatelet drugs that were extensively evaluated in the 1970s and 1980s. Their mechanisms of action are not as well understood as that of aspirin. Dipyridamole appears to increase platelet cyclic-AMP levels limiting the response of platelets to pro-aggregatory stimuli, while sulfinpyrazone is a weak reversible inhibitor of cyclo-oxygenase. Overall, these non-aspirin platelet inhibitors have not proven particularly effective and the search for more potent antiplatelet drugs has continued. Several new and potentially useful drugs have now been identified and are being evaluated.

The 'new' antiplatelet drugs
The new antiplatelet drugs have only been studied in combination with, and not in comparison to, aspirin.

Platelet glycoprotein IIb/IIIa receptor antagonists
An important outcome of recent research into platelet biology has been the characterisation of the platelet receptor for fibrinogen. This glycoprotein receptor, known as the IIb/IIIa receptor, is critical for platelet aggregation. Fibrinogen molecules bind to these receptors to form bridges between adjacent platelets allowing them to aggregate. Blockade of this receptor prevents fibrinogen binding and thus platelet aggregation, irrespective of the stimulus initiating aggregation (Fig. 1).

The identification of the platelet glycoprotein IIb/IIIa receptor led to the development of receptor antagonists (Table 1). These drugs are designed to block the receptor and prevent platelet aggregation. The first drug of the class was a monoclonal antibody (abciximab) directed against the receptor. Other drugs in this class are based around an amino acid sequence (arginine-glycine-aspartate or RGD), present in fibrinogen and other adhesion molecules, which acts as a recognition site for binding to the receptor. The 3 most extensively evaluated drugs in this group are Integrelin, lamifiban and tirofiban. Several other drugs in this class are at various stages of evaluation, including xemlofiban - an orally active drug that is a potent receptor antagonist.

Fig. 1

Schematic diagram of the role the platelet glycoprotein IIb/IIIa receptor in platelet aggregation. Fibrinogen molecules bind to the glycoprotein IIb/IIIa receptors to form bridges between adjacent platelets. The glycoprotein IIb/IIIa receptor antagonists block the interaction of the platelet receptor with fibrinogen, preventing aggregation.

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Table 1

Glycoprotein IIb/IIIa receptor antagonists recently evaluated in clinical trials

Agent Type
Abciximab (previously chimeric 7E3) monoclonal antibody
Integrelin peptide
Lamifiban (previously Ro 44-9883) peptide derivative
Tirofiban (previously MK-383) peptide derivative
Xemlofiban orally active peptide derivative

Ticlopidine
Ticlopidine is a 'broad-spectrum' antiplatelet agent that has recently emerged as a useful drug, particularly in ischaemic cerebrovascular disease. Unlike aspirin, ticlopidine does not affect the cyclo-oxygenase pathway. Its mechanism of action is still uncertain, but it appears to interfere with the interaction between fibrinogen and the platelet glycoprotein IIb/IIIa receptor. Ticlopidine also differs from aspirin as its effects take up to 48-72 hours to begin. These effects are not reversible, requiring up to a week to dissipate completely. Adverse effects of ticlopidine include diarrhoea (reported in up to 20% of patients), rash and neutropenia. The reduction in white cell count occurs in approximately 2% of patients and can be life-threatening. Accordingly, it is generally recommended to perform regular white cell counts during the first 3 months of therapy, after which the risk of neutropenia declines. A number of large studies have established an important role for ticlopidine in the treatment of transient ischaemic attacks and ischaemic stroke.

Ridogrel
Although the primary action of aspirin is to block TXA2 formation, it also inhibits formation of prostacyclin - a natural inhibitor of platelet aggregation (Fig. 2). Ridogrel, the most recent antiplatelet drug to enter the clinical arena, circumvents this limitation of aspirin by blocking the arachidonic acid pathway at two key sites. The drug is a combined TXA2 synthase inhibitor and prostaglandin endoperoxide receptor antagonist. The inhibition of TXA2 synthase blocks TXA2 production and allows excess prostaglandin endoperoxides to accumulate. In turn, these intermediary prostaglandins can be diverted to the pathway for prostacyclin formation, further inhibiting platelet aggregation. However, the endoperoxides also possess their own platelet aggregatory activity. The second key antiplatelet action of ridogrel is to block the platelet receptors for prostaglandin endoperoxide. This counteracts the pro-aggregatory activity of the prostaglandin endoperoxides, and allows the endoperoxides to be diverted to prostacyclin production. With this more specific effect on the arachidonic acid pathway, ridogrel has been shown to have greater antiplatelet activity than aspirin in human volunteers. Clinical experience with this drug is still relatively limited, although it has already undergone small- scale clinical trials in patients with myocardial infarction and unstable angina.

Fig. 2
Schematic overview of the arachidonic acid pathway leading to thromboxane A2 (TXA2) and prostacyclin production and the effects of these prostaglandins on platelet aggregation. The site of mechanism of action of asprin and ridogrel are shown.

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Clinical applications of antiplatelet drugs (Table 2)

Coronary angioplasty
Despite the recent development of the glycoprotein IIb/IIIa receptor inhibitors, several trials have already been completed with these drugs. The Evaluation of abciximab in the Prevention of Ischemic Complications (EPIC) trial was the first large-scale trial to show a benefit with glycoprotein IIb/IIIa receptor blockade in high-risk angioplasty.1,2 The study, which enrolled 2099 angioplasty patients at increased risk of abrupt vessel closure, found a 35% reduction in acute ischaemic complications with a bolus and 12-hour infusion of abciximab. This monoclonal antibody also significantly reduced the need for repeat revascularisation procedures and subsequent myocardial infarction over the ensuing 6 months. More recently, two large studies of abciximab (in patients with refractory unstable angina awaiting coronary angioplasty and in patients undergoing routine angioplasty) were halted prematurely because proof of benefit was evident at the interim analysis.

Table 2

Summary of the current proof of benefit for the use of antiplatelet drugs
in various cardiovascular conditions

Coronary
angioplasty
Acute myocardial
infarction
Unstable
angina
Transient
ischaemic
attack/stroke
Aspirin + + + +
Dipyridamole ? ? ? ?
Sulfinpyrazone ? ? ? ?
Abciximab * ? ? ?
Integrelin * ? ? ?
Ticolopidine * ? * +
Ridogrel ? * ? ?

? - no or uncertain benefit
* - probable benefit
+ - definite and proven benefit

Integrelin has been studied in a large trial of 4100 patients undergoing routine coronary angioplasty.3 While the magnitude of benefit with Integrelin was not as great as with abciximab, there was still a strong trend towards reduced ischaemic complications assessed at 30 days.

The results of these trials appear to establish a place for glycoprotein IIb/IIIa receptor inhibition in coronary angioplasty, especially in patients identified as 'high-risk', and that the drug class as a whole is likely to become an important additional tool in the treatment of coronary stenoses.

Aspirin was included in both the treatment and control groups of all the trials of glycoprotein IIb/IIIa receptor inhibitors in coronary angioplasty. Aspirin is already a well-established and integral component of angioplasty for the prevention of abrupt closure. The new drugs are intended to supplement and enhance the effects of aspirin, not replace it. Even in the presence of the substantive benefit of glycoprotein IIb/IIIa receptor inhibition in both high-risk and routine angioplasty, aspirin remains a mandatory part of all angioplasty procedures.

Ticlopidine has also been used extensively in combination with aspirin for prevention of subacute thrombosis after intracoronary stent insertion. Several non-randomised series have demonstrated acceptably low rates of thrombosis with this antiplatelet combination.4 Randomised studies comparing aspirin, warfarin and ticlopidine are currently ongoing.

Acute myocardial infarction
There is now universal acceptance of the role of aspirin in acute myocardial infarction. The large-scale Second International Study of Infarct Survival (ISIS-2) thrombolytic trial5 showed the absolute benefit of aspirin in preventing death and reinfarction. As a result, all subsequent trials of newer therapies for acute myocardial infarction have also incorporated aspirin.

The glycoprotein IIb/IIIa receptor antagonists have been evaluated in a small number of pilot trials in acute myocardial infarction.6 Although not primarily an infarct trial, the EPIC trial included 64 patients who underwent angioplasty for acute myocardial infarction. (Patients with evolving infarction have active and recent arterial thrombosis and often experience reocclusion and reinfarction.) In this subgroup of patients from the EPIC trial, treatment with abciximab reduced acute ischaemic complications by 83%. Similarly, positive results were obtained in a pilot trial of Integrelin as adjunctive therapy to thrombolysis. While by no means conclusive, these early data suggest a potentially important role for this class of drug in the setting of acute myocardial infarction. Several trials with various glycoprotein IIb/IIIa receptor antagonists in acute myocardial infarction are currently underway.

There have been no major trials evaluating ticlopidine after acute myocardial infarction. This indication is still experimental. In contrast, ridogrel has been found to be more effective than aspirin alone in reducing ischaemic events following streptokinase thrombolysis in a trial of 907 patients with acute myocardial infarction. While adjunctive therapy with ridogrel is still under active investigation, there is little evidence of a clinically important role for either dipyridamole or sulfinpyrazone in acute myocardial infarction.

Unstable angina pectoris
As in myocardial infarction, aspirin is now a routine and accepted treatment for unstable angina. Pooled results of several trials of aspirin in unstable angina show a 30-60% reduction in the risk of death or subsequent myocardial infarction. In contrast, sulfinpyrazone and dipyridamole do not have any clearly established role.

Pilot trials with various glycoprotein IIb/IIIa receptor antagonists including lamifiban, abciximab and Integrelin have all indicated a benefit that is additive to aspirin. The largest of these pilot trials evaluated lamifiban in 365 patients with unstable angina. The occurrence of death or myocardial infarction in the first 5 days was more than halved. Definitive proof of benefit from large-scale randomised trials is still unavailable, although several such trials are underway. Until more evidence is available, the routine use of glycoprotein IIb/IIIa antagonists in acute coronary syndromes in general, and in unstable angina in particular, cannot be recommended.

Ticlopidine is also effective in reducing subsequent ischaemic events in patients with unstable angina, and may be considered an effective alternative in patients intolerant of aspirin.

Other indications
Apart from the use of glycoprotein IIb/IIIa receptor antagonists in coronary angioplasty, the strongest indication for an alternative antiplatelet to aspirin is the use of ticlopidine in secondary stroke prevention. Two large trials, conducted in the mid-1980s, found that ticlopidine reduced the overall risk of stroke in patients with previous transient ischaemic attacks or minor stroke.7,8 Patients who appeared to derive particular benefit were those with previous minor stroke, vertebrobasilar symptoms and those in whom aspirin had previously failed.

There is little evidence to support the use of dipyridamole in cardiovascular disease, although it may have a small place in patients allergic to or intolerant of aspirin. Its combined use with aspirin has been advocated in maintaining long-term coronary saphenous vein graft patency, but it is unlikely that dipyridamole offers any additive benefit over aspirin alone.

Future prospects
While aspirin still retains its status as the 'front-line' antiplatelet drug, the newer drugs now offer potentially greater and more specific control over platelet function. The blockade of the platelet glycoprotein IIb/IIIa receptor the final common pathway to platelet aggregation is effective in the setting of coronary angioplasty and is already being used widely in high-risk or complex angioplasty. It also appears likely that these drugs will be useful in acute coronary syndromes. The orally active ticlopidine has emerged as an effective alternative for patients intolerant of aspirin, and is superior to aspirin for secondary stroke prevention. Yet, these drugs are significantly more expensive than aspirin, and their eventual role in the clinical arena will ultimately depend on both their efficacy and their cost-effectiveness. This greater cost of ticlopidine, compared with aspirin, is one factor which has restricted its availability under the Pharmaceutical Benefits Scheme.

Several more drugs are being developed, aimed at controlling different phases of platelet function such as platelet adhesion. As we approach the next millennium, it is envisaged that our increased understanding of platelet function, coupled with advances in technology and drug manufacture, will result in even greater improvements in the therapeutic control of platelet thrombus.

References
1 . The EPIC Investigation. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty [see comments]. N Engl J Med 1994;330:956-61. Comment in: N Engl J Med 1994;330:1006-7.

2 . Topol EJ, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worley S, et al. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. The EPIC Investigators [see comments]. Lancet 1994;343:881-6. Comment in: Lancet 1994;343:1434-5.

3 . Tcheng JE, Lincoff AM, Sigmon KN, Kitt MM, Califf RM, Topol EJ. Platelet glycopotein IIb/IIIa inhibition with Integrelin during percutaneous coronary intervention: The IMPACT II trial. Circulation 1995;92(8 Suppl):I543.

4 . Colombo A, Hall P, Nakamura S, Almagor Y, Maiello L, Martini G, et al. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance [see comments]. Circulation 1995;91:1676-88. Comment in: Circulation 1995;91:1891-3.

5 . ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-60.

6 . Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 1995;332:1553-9.

7 . Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, Harbison JW, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke [see comments]. Lancet 1989;1:1215-20. Comment in: Lancet 1989;2:442-3.

8 . Hass WK, Easton JD, Adams HP Jr, Pryse-Phillips W, Molony BA, Anderson S, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group [see comments]. N Engl J Med 1989;321:501-7. Comment in: N Engl J Med 1990;322:404-5.

Self-test questions

The following statements are either true or false (click here for the answers)

1. Inhibition of prostacyclin formation by aspirin may increase platelet aggregation.

2. Ticlopidine may be beneficial in acute myocardial infarction because of its rapid onset of action.



First published online: October - 1996