Antiplatelet Drugs

A role in the prevention and acute treatment of arterial thrombosis

Antiplatelet agents have proven efficacy in the acute treatment and prevention of arterial thrombosis.⁹⁵ As with anticoagulants, all available antiplatelet agents increase the risk of bleeding. Clinical decision-making must always balance the risks and benefits of treatment.

The antithrombotic effect of Aspirin

Aspirin irreversibly inhibits the COX-1 enzyme, thereby blocking production of thromboxane A2 (TXA₂) in platelets.¹⁰⁷ TXA₂ is a potent platelet activator (along with ADP, collagen, and thrombin). Platelets cannot synthesise new proteins, so a single dose of Aspirin suppresses TXA₂ production for the life of the platelet.

Aspirin exerts a maximal antithrombotic effect at a dose of 100 mg, which is considerably lower than the dose typically used for analgesic or anti-inflammatory effects. Low-dose Aspirin therapy has a modest antithrombotic effect, preventing approximately 25% of cardiovascular events when used to prevent recurrent coronary thrombosis. A possible reason for this modest effect is that other platelet activators, not inhibited by Aspirin, may compensate for the lack of TXA₂.^{107, 108}

Because of its antiplatelet effects and its suppressive effects on gastric mucosal protection, gastrointestinal (GI) bleeding is the major side effect of Aspirin use. The incidence in patients without other risks for GI bleeding is relatively low (1 to 2 per 1000 patient-years), so for many patients the benefits of low-dose Aspirin in secondary cardiac prevention far outweigh the risks.¹⁰⁷

Thienopyridines

Thienopyridines currently in clinical use are clopidogrel, prasugrel and ticlopidine. These antiplatelet drugs are marginally superior to Aspirin in preventing atherothrombosis in the cerebral and peripheral arteries but not in the coronary arteries. In patients at high risk of recurrent coronary ischaemia, thienopyridines are often used in combination with Aspirin for a synergistic antithrombotic effect.¹⁰⁸

Clopidogrel exerts its antiplatelet effects by irreversibly binding to the ADP receptor P2Y₁₂.¹⁰⁷ Because the onset of clopidogrel action is slow, a loading dose is used when rapid antithromboitc effects are needed, as in acute coronary syndrome. Repeated daily doses produce a steady state after four to seven days, and platelet function returns to normal a week after the last dose.¹⁰⁷

Ticlopidine, an agent older than clopidogrel, causes neutropenia in 2% of patients, while clopidogrel does not. For this reason, clopidogrel is the preferred drug in this class.¹⁰⁸ The major side effect of clopidogrel, like Aspirin, is GI bleeding. The haematologic disorder thrombotic thrombocytopenic purpura is a rare adverse event associated with clopidgrel.¹⁰⁹

Some studies indicate that clopidogrel may be less effective in patients taking proton pump inhibitors (PPIs).²²⁴ Based on these data, in May 2009 the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended that product information for all clopidogrel-containing medicines be amended to discourage concomitant use with PPIs.¹⁷¹ However, based on a subsequent review of the available data, the CHMP concluded in March 2010 that there were no solid grounds to extend the warning to other PPIs.¹⁷² The class warning for all PPIs was rescinded, and the committee updated its recommendations to discourage concomitant use of clopidogrel only with the PPIs omeprazole and esomeprazole.^{266, 172} On 27 October 2010, the FDA re-issued its warning against the use of Plavix with omeprazole.²⁷⁵

Prasugrel is a newer thienopyridine, approved by the EMA and the FDA in 2009 for reduction of thrombotic cardiovascular events, including stent thrombosis in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). ^{184, 265} Prasugrel has a structure and mode of action similar to that of clopidogrel, but, unlike clopidogrel, it requires only one oxidative step to be converted into its active form.²⁴⁴ This singular step may lessen the variability in response to prasugrel, compared with clopidogrel.²⁴⁴ In clinical studies, prasugrel was shown to prevent heart attacks more effectively than clopidogrel, although in some trials there was more major bleeding with prasugrel.²⁴⁴

Cyclo-pentyl-triazolo-pyrimidines (ticagrelor)

On 6 December 2010, the manufacturer of ticagrelor, an antiplatelet medication in the cyclo-pentyl-triazolo-pyrimidine class, announced EMA approval to market the drug as a treatment for ACS.¹⁶⁰ Ticagrelor is a direct-acting inhibitor of the platelet P2Y12 inhibitor, and, unlike thienopyridines, its antagonist effect on this receptor is reversible.²⁷⁹ Ticagrelor was compared to clopidogrel in the randomised, double-blind PLATO (Study of PLATelet Inhibition and Patient Outcomes) trial. Over 18,000 hospitalised patients with ACS were studied. Study participants also took Aspirin, unless they were Aspirin-intolerant.²⁷⁹

At 12 months, the composite primary endpoint of death from vascular causes, myocardial infarction, or stroke had occurred in 9.8% of those in the ticagrelor group and 11.7% of those in the clopidogrel group (hazard ratio, 0.84; P<0.001). The death rate from any cause also was lower with ticagrelor than with clopidogrel (4.5% versus 5.9%, P<0.001). There was no significant difference in the rates of major bleeding between the treatment groups, but the rate of major bleeding not related to coronary artery bypass grafting was higher with ticagrelor. (4.5% versus 3.8%, P=0.03).²⁷⁹

Glycoprotein IIb/IIIa complex inhibitors

The glycoprotein IIb/IIIa complex (GpIIb/IIIa) is the primary receptor involved in platelet aggregation.^{107, 108} This receptor establishes links to other platelets by binding to fibrinogen. Three GpIIb/IIIa-inhibiting drugs are currently available for clinical use: abciximab, tirofiban, and eptifibatide. Abciximab is a humanised immunoglobulin fragment, while tirofiban and eptifibatide are smaller molecules that bind to GpIIb/IIIa, competing with fibrinogen. All three drugs must be administered intravenously. They are used to achieve antithrombotic effect during percutaneous coronary interventions and to treat acute coronary syndrome. The inhibitory effect of these medications is reversible. Comment SH: Please re-check. Abciximab is normally seen as an irreversible inhibitor since it binds irreversibly to the platelets!

As with other antithrombotic agents, bleeding is the most common adverse event. Transient severe thrombocytopenia has also been reported, most commonly with abciximab.

Phosphodiesterase inhibitors

Another class of antiplatelet drugs works by inhibiting phosphodiesterase. Cyclic AMP and GMP function as intracellular signalling agents to inhibit platelet activation and aggregation. Phosphodiesterase inhibitors exert an antithrombotic effect by increasing levels of these cyclic nucleotides inside the platelet.^{107, 110}

The phosphodiesterase inhibitor dipyramidole is available as a sustained-release oral agent. Dipyramidole is prescribed in combination with warfarin to prevent cardiac emboli in patients with mechanical heart valves and in combination with Aspirin for secondary stroke prevention. Cilostazol inhibits platelet phosphodiesterase 3 and blocks platelet aggregation stimulated by ADP. It is indicated for symptomatic peripheral artery disease.

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Article references

95 - Mackman N. Triggers, targets and treatments for thrombosis. Nature. 2008;451(7181):914-918.
107 - Messmore HL Jr, Jeske WP, Wehrmacher W, et al. Antiplatelet agents: current drugs and future trends. Hematol Oncol Clin North Am. 2005;19(1):87-117, vi.
108 - Roth GJ. Antiplatelet therapy. In: Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006:1725-1737.
109 - Plavix [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2007.
224 - Last EJ, Sheehan AH. Review of recent evidence: potential interaction between clopidogrel and proton pump inhibitors. Am J Health Syst Pharm. 2009;66(23):2117-2122.
171 - Committee for Medicinal Products for Human Use (CHMP). Public statement on possible interactions between clopidogrel and proton pump inhibitors. London, England: European Medicines Agency; 2009.
172 - Committee for Medicinal Products for Human Use (CHMP). Monthly report, March 2010. London, England: European Medicines Agency; 2010.
266 - Summary of product characteristics for Plavix. London, England: European Medicines Agency; 2010.
275 - US Food and Drug Administration. Information on clopidogrel bisulphate (marketed as Plavix). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm190836.htm. Accessed December 15, 2010.
184 - Effient [package insert]. Indianapolis, IN: Eli Lilly & Company, Inc.; 2010.
265 - Summary of product characteristics for Effient. London, England: European Medicines Agency; 2010.
244 - Mousa SA, Jeske WP, Fareed J. Antiplatelet therapy prasugrel: a novel platelet ADP P2Y12 receptor antagonist. Clin Appl Thromb Hemost. 2010;16(2):170-176.
160 - AstraZeneca Pharmaceuticals Inc. European Commission approves Brilique (ticagrelor tablets). http://www.astrazeneca.com/Media/Press-releases/Article/European-Commission-Approves-Brilique. Accessed December 15, 2010.
279 - Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. New Engl J Med. 2009;361(11):1045-1057.
110 - Beebe HG, Dawson DL, Cutler BS, et al. A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial. Arch Intern Med. 1999;159(17):2041-2050.

Aspirin: The brand name of acetylsalicylic acid (ASA), an antithrombotic medication that prevents thrombosis by inhibiting the activity of platelets – a component of blood that helps to prevent blood loss.
Platelet: (Thrombocyte) Cell circulating in the blood that is involved in the cellular mechanisms of primary haemostasis leading to the formation of blood clots. When a blood vessel is injured, platelets gather at the site of injury and stick together to form a plug, thereby preventing blood loss.
Clopidogrel: Oral antiplatelet agent used in the treatment of coronary artery disease, peripheral vascular disease and cerebrovascular disease.
Acute coronary syndrome: This is an umbrella term used to cover any group of clinical symptoms compatible with acute myocardial ischaemia (chest pain due to insufficient blood supply to the heart muscle that results from coronary artery disease). Acute coronary syndrome covers the spectrum of clinical conditions ranging from unstable angina to STEMI and NSTEMI.
Committee for Medicinal Products for Human Use: The CHMP is responsible for preparing the European Medicines Agency’s (EMEA) opinions on all questions concerning medicinal products for human use. Assessments conducted by the CHMP are based on purely scientific criteria and determine whether or not the products concerned meet the necessary quality, safety, and efficacy requirements.
Myocardial infarction: Destruction of heart tissue due to reduced blood flow to the heart. Also known as a heart attack. It usually results from coronary artery disease and is more severe than angina.
Warfarin: A vitamin K antagonist. Most commonly used oral anticoagulant in chronic prevention or treatment of VTE.