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  • Cardiovascular Medicine is published by MDPI from Volume 28 Issue 1 (2025). Previous articles were published by another publisher in Open Access under a CC-BY (or CC-BY-NC-ND) licence, and they are hosted by MDPI on mdpi.com as a courtesy and upon agreement with Editores Medicorum Helveticorum (EMH).
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30 August 1998

Platelet Inhibitory Drugs: Present Status and New Developments

and
1
Department of Medicine, Kantonsspital Baden, Baden, Switzerland
2
Division of Cardiology, Department of Medicine, University Hospital of Berne, Bern, Switzerland
*
Author to whom correspondence should be addressed.
Cardiovasc. Med.1998, 1(2), 111-116;https://doi.org/10.3390/cardiovascmed1020028
Version Notes

Summary

For many years, aspirin has set the standard for platelet inhibition in cardiovascular prophylaxis and therapy. With the advent of newer, invasive techniques and new potent antiplatelet agents, antiplatelet therapy will be likely to change and diversify in the near future. This brief review summarises present and future developments. Essentially, two trends are crystallizing: (a) the combination of established antiplatelet agents such as aspirin with ticlopidin or newly with others such as clopidogrel and (b) the platelet glycoprotein 11b/IIIa antagonists in their different, optimized molecular forms and dosages.

Zusammenfassung

Seit vielen Jahren stellt Aspirin die Standardmedikation zur Plättchenhemmung in der kardiovaskulären Prophylaxe und Therapie dar. Durch die Einführung von neuen, invasiven Techniken und neuen potenten Aggregationshemmern wird Sich die Behandlung mit Plättchenhemmern in naher Zukunft wahrscheinlich verändern.
Diese kurze Review fasst gegenwärtige und künftige Entwicklungen auf diesem Gebiet zusammen. Zwei Trends kristallisieren Sich besonders heraus: a) die Kombination von etablierten Aggregationshemmern wie Aspirin mit Ticlopidin Oder anderen, wie Clopidogrel, und b) die Blutplättchen Glykoprotein-llb/ Ila-Antagonisten in ihren unterschiedlichen, optimierten molekularen Formen und Dosierungen.
The principles of platelet activation and the potential of pharmacological interventions are summarised and illustrated in figure 1: multiple agonists, such as thrombin, collagen or ADP, but also turbulent flow with increased shear rates and the adhesion itself will lead to platelet activation. Agonist effects may be potentiated by endogenous platelet activation pathways such as the release of ADP, serotonin and the production of thromboxane. Combinations of so-called "weak" agonists (ADP, epinephrine, PAF) or low concentrations of "strong" agonists (thrombin, collagen) will act synergistically and result in platelet activation, the exposure of competent GPIIb/IIIa receptors, with subsequent fibrinogen binding, and in primary, reversible and then secondary, irreversible aggregation with release reaction. Platelet thrombus stabilisation and liberation of procoagulant activity (microvesicles) are further events in the course of platelet activation which are subject of current intensive study and of potential therapeutic options. The latter are also illustrated in Figure 1.
Figure 1. Pathway of platelet activation: platelet adhesion and aggregation is a key step in vascular repair following vessel wall injury. Several stimuli cause platelet activation, including substances in the milieu of plaque rupture such as ADP, adrenalin, collagen, and thrombin. In addition, mechanical stimuli such as shear forces cause platelet activation. Activation of platelet occurs through several internal pathways of which one is thromboxane A2 production in the arachidonic acid pathway which can be blocked irreversible by aspirin. However, platelet aggregation can still occur through TxA2-independent pathways, particularly at high agonist concentrations. The final common pathway of platelet activation is the expression of the activated platelet GP 11b/IIIa receptor. Therefore, agents that block the glycoprotein GP 11b/IIIa receptor may inhibit platelet aggregation completely irrespective of the agonist.
Present and future potential therapeutic interventions with platelet inhibitory drugs, their possibilities and problems are depicted. Aspirin and — less known — the thromboxane receptor inhibitors are able to inhibit low dose agonist induced platelet activation of a number of platelet activating agents but will not prevent activation by higher concentrations. Specific inhibition of pathways may be achieved by antithrombins or the thienopyridines (ticlopidine or clopidogrel) [5,34], which interfere with the ADP and collagen-pathway perhaps with GPIIb/IIIa and may reduce shear-induced activation [7].
Combinations of antagonists will have additive or perhaps synergistic activities as has been shown clinically for combinations of aspirin with ticlopidin [9] and perhaps of aspirin with dipyridamole ([6], study dosages: 2 × 25 mg ASA and 2 × 200 mg dipyramidole). Aspirin will be tested in combination with clopidogrel in future studies.
A completely different concept is the inhibition of aggregation by the 11b/IIIa antagonists, which inhibit the final common pathway of platelet activation. Dose-dependent full inhibition irrespective of the agonist involved offers a potent and clinically tailored protection at the expense of bleeding at the high degree of inhibition.
The bottom line questions, however, for present and future antiplatelet therapies will remain the following:
  • What is the number needed to treat (NNT, effect) and what is the number needed to harm (NNH, side effects) in a given, well characterised target population?
  • Are effects of the new agent studied for primary or secondary prophylaxis or for acute treatment? For which endpoint precisely?
  • Is the preventive benefit continuing after short-term treatment applicable to both men and women? What is the effect in certain subpopulations (old age etc.)? Are there subgroups that fare better with one antiplatelet agent than with another depending on the site of disease (neurovascular, cardiovascular and peripheral vascular disease)? Local vascular factors may modulate mechanisms of atherothrombotic disease. Is the enteral and parenteral application possible? What are the pharmacodynamics? What if the patient is already on aspirin and has suffered an event? Should aspirin be continued in addition?
In the case of aspirin the data are well established and — as an example — they may be summarised as follows:
The NNT for primary prophylaxis in the physicians' health study [9] was 550 for myocardial infarction and 3440 for death. For secondary prophylaxis after myocardial infarction or other events, it is 62, respective 186 [10]; even patients in their seventies and octogenerians will still profit from secondary prophylaxis [11]. Patients will benefit from the treatment during myocardial infarction and stroke [1,2,3]. The NNH is 200 for severe bleeding and 500–1000 for intracerebral bleeding [5,9,12,13]. The initial dose for treatment should be at least 250 mg of non-retarded aspirin, the maintenance dose in cardiology and peripheral vascular disease is usually 100 mg of retarded aspirin, for cerebrovascular indications there is a widespread consensus for 250-300 mg aspirin daily among neurologists; whether anti-inflammatory properties of this dose are operational in addition to the effective anti-platelet dose given the increased risk of cardiovascular events in patients with elevated CRP [15] remains to be established. On the other hand, theoretical evidence, some clinical studies, and the dose-dependent frequency of side effects suggest that much lower doses might be at least as adequate: presystemic, continuous acetylation of the platelets between gut and liver will inhibit the platelet cyclooxygenase but not the prostacyclin production of endothelial cells of the vascular bed due to an almost complete first pass effect [16]. The Swedish aspirin low dose trial (SALT) [12] and the Dutch TIA trial [13] have successfully used 30 and 50 mg of aspirin with at least equal results as in the higher dose group, however, with less bleeding.
Thienopyridines are somewhat more effective than aspirin but are more expensive and ticlopidin carries the risk of important hematological and gastrointestinal side effects. These side effects appear to have now been eliminated with the introduction of clopidogrel. This agent reduced the combined endpoint compared to aspirin significantly from 53 to 42 (NNT) [5]. Subgroup analysis in this study might suggest that clopidogrel is particularly effective in preventing peripheral vascular disease. Therefore, patients suffering an event while under treatment with aspirin may be considered for a clopidogrel therapy. However, enthusiasm must be tempered because 200 patients must be switched from aspirin in order to spare one event.
This leads us to the questions of the potential alternatives ("What do we have?" ) and of the future directions of antiplatelet therapy ("What do we need?").
The following 3 principles likely to be further applied in the future:
1.
Combinations of two or more "weak" antagonists to block several independent pathways. Examples which have already shown their effectiveness include:
–
aspirin and ticlopidin after placement of intracoronary stents [8];
–
aspirin and dipyridamole in the secondary prophylaxis of stroke [6];
–
aspirin and LMW heparin [4].
2.
The GP 11b/IIIa antagonists (inhibiting platelet fibrinogen binding and platelet aggregation) individually dosed (adapted according to the clinical situation) and given over the proper route (i.v. or p.o.).
3.
GP 1b antagonists (inhibiting von Willebrand factor binding to platelets and platelet adhesion) would have the potential of being particularly effective in the pathologically high shear rate situation of high grade stenoses, but to a lesser extent in the physiological hemostatic situation, thus potentially approaching the ideal of platelet inhibition without the bleeding risk.

Monitoring of antiplatelet therapy

Monitoring of the occupied receptors in a given individual will become an increasingly important issue. A simple, rapidly performed bed-side test is a necessity because the available tests such as bleeding time, aggregation studies (and perhaps flow cytometric examinations) do not reflect the degree of required platelet inhibition or are methodologically difficult. As illustrated in Figure 2, a 90—95% occupancy of the GP 11b/IIIa which appears to be required in high grade stenoses such as in unstable angina pectoris, cannot be controlled or identified by the bleeding time; (which will be over 20—30 minutes long, cumbersome and carries a number of well known methodological problems [15]). Platelet aggregation studies with ADP and collagen are not possible at this upper range of receptor occupancy. A simple bed-side agglutination test has been proposed [26]. If the problems of individual variability of absorption and the variable percentage of receptor occupancy, respectively its analysis can be solved, an individually tailored antiplatelet therapy appears possible in the future; one speculative hypothesis could be that for primary prophylaxis as little as 50—70% receptor occupancy without relevant bleeding as in the case of the heterozygous Glanzmann's thrombasthenia could suffice. Secondary prophylaxis may require 75—85% depending on the severity of the disease whereas therapy may approach 90—95% receptor occupancy. Particularly, the latter will require careful, reliable and rapid monitoring to prevent bleeding and inadequate therapy. A high degree of inhibition will require a very reproducible absorption and stable and predictive plasma levels.
Figure 2. Number of competent IIb/IIIa receptors per platelet: effects on aggregation, bleeding time and coronary stenosis in unstable angina and in animal models. The figure illustrates that the bleeding time remains normal with less than 50% of competent receptors available on platelets, it will then rapidly approach 30 minutes at approximately 15 – 20% or less of the receptors available. The aggregation with ADP or collagen will be reduced starting at approximately 60% of the available receptors and will be completely inhibited at approximately 25 – 30% of the receptors available. This means that the situation of the unstable angina and similar animal models in primates and dogs [28,29] are likely not to be reflected by the methods of aggregation and bleeding time. Therefore, it is urgent to have a simple platelet function assay to assess glycoprotein IIb/IIIa receptor blockade, e.g. as proposed by Coller et al. [26]. The figure is a summary of the data presented in [30].
The winner of the race of type I vs. type Il therapy will have the satisfaction of having set the standard (if better than aspirin) with which the competitors will have to treat their control population. Alternatively, it appears possible that one regimen will be preferable for one disease (or degree of stenosis) while the other will prove superior in a different setting.

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