Category:Antiplatelet agents

An antiplatelet agent is a medicine that interferes with platelet activation, adhesion, or aggregation, reducing the propensity of platelets to form a thrombus on a damaged or atherosclerotic vascular surface. The category is distinct from the anticoagulants, which act on the coagulation cascade rather than on platelet function, although the two are often co-prescribed (and their bleeding risks are additive). The antiplatelet agents are the foundation of secondary prevention in atherothrombotic disease (coronary, cerebrovascular, peripheral arterial), are central to the management of acute coronary syndromes, and are essential to the safe deployment of intravascular devices (coronary stents, mechanical heart valves with thrombogenic surfaces, ventricular assist devices).

The category begins with aspirin. The antiplatelet effect of acetylsalicylic acid, taken since 1899 as an analgesic, antipyretic, and anti-inflammatory, was identified by Harvey Weiss at Roosevelt Hospital in New York in 1967, who showed that ingestion of aspirin in a normal adult abolished the platelet response to collagen and prolonged the bleeding time;^[1] the British pharmacologist John Vane four years later demonstrated the mechanism: aspirin irreversibly acetylates cyclooxygenase (COX-1) in the platelet, which lacks a nucleus and cannot resynthesize the enzyme, eliminating the platelet's ability to produce thromboxane A2 for the lifespan of the platelet (approximately ten days). The 1988 ISIS-2 trial of 17,187 patients with suspected acute myocardial infarction randomised to aspirin, intravenous streptokinase, both, or neither showed a 23 percent reduction in 35-day vascular mortality with aspirin alone, additive to the 25 percent reduction with streptokinase alone, and the combination achieved a 42 percent reduction; the trial established daily 75-to-100 mg aspirin as the foundational secondary-prevention medicine.^[2]

The second class of antiplatelet was the thienopyridine family of ADP-receptor antagonists. Ticlopidine, introduced in 1991, irreversibly inhibited the platelet P2Y12 receptor for adenosine diphosphate; its development was complicated by a rare but devastating thrombotic thrombocytopenic purpura (TTP) and an idiosyncratic neutropenia. Clopidogrel (Sanofi/BMS, 1997), a closely related prodrug requiring CYP2C19 activation, replaced ticlopidine with a substantially better safety profile and became, in combination with aspirin, the standard "dual antiplatelet therapy" (DAPT) following coronary stent implantation. The 2001 CURE trial established the benefit of clopidogrel + aspirin over aspirin alone in non-ST-elevation acute coronary syndromes.^[3] Prasugrel (Daiichi Sankyo/Lilly, 2009) and ticagrelor (AstraZeneca, 2011) followed with more potent, faster-onset, and (for ticagrelor) reversible P2Y12 blockade; the TRITON-TIMI 38 and PLATO trials established their superiority over clopidogrel in selected acute-coronary-syndrome populations, at the cost of a modest increase in major bleeding.

A second mechanism is intravenous glycoprotein IIb/IIIa inhibition. The platelet GP IIb/IIIa receptor is the final common pathway by which platelets cross-link to each other through fibrinogen bridges; its monoclonal antibody abciximab (Centocor, 1994), and the small-molecule inhibitors eptifibatide (1998) and tirofiban (1998), were used extensively during high-risk percutaneous coronary intervention in the early 2000s; their clinical role has narrowed substantially as the oral P2Y12 inhibitors have improved.

The most recent mechanistic addition is protease-activated-receptor-1 (PAR-1) inhibition. The thrombin receptor on the platelet surface, activated by thrombin's proteolytic cleavage of its N-terminus, drives a third independent pathway of platelet activation. Vorapaxar (Merck, 2014), the first PAR-1 antagonist, demonstrated a modest reduction in atherothrombotic events when added to aspirin and clopidogrel in patients with prior myocardial infarction or peripheral arterial disease (TRA 2°P-TIMI 50 trial); its clinical use has been limited by the bleeding-risk increment of triple antiplatelet therapy and by its contraindication in patients with prior stroke.

The duration of dual or triple antiplatelet therapy is one of the most actively investigated clinical decisions in cardiovascular medicine. Modern second-generation medicine-eluting stents allow DAPT durations as short as one month in selected lower-risk patients, balancing the residual stent-thrombosis risk against the cumulative bleeding cost of prolonged treatment. The CHARISMA, DAPT, PEGASUS, TWILIGHT, and HOST-EXAM trials have together defined a complex set of patient-specific algorithms for DAPT duration after acute coronary syndrome and after elective PCI; the contemporary trend has been toward shorter DAPT followed by either aspirin or P2Y12 monotherapy, with monotherapy with the more potent P2Y12 inhibitor (rather than the historical default of aspirin) increasingly favoured.

By target:

• Cyclooxygenase-1 inhibitors: aspirin (low-dose for antiplatelet effect, 75-100 mg daily)
• P2Y12 inhibitors (ADP-receptor antagonists):
  • Thienopyridine prodrugs (irreversible, require hepatic activation): clopidogrel (Plavix), prasugrel (Effient), ticlopidine (largely retired)
  • Non-thienopyridine direct-acting reversible: ticagrelor (Brilinta), cangrelor (intravenous)
• Glycoprotein IIb/IIIa receptor antagonists (intravenous, in-hospital use):
  • Abciximab (monoclonal antibody Fab), eptifibatide (synthetic peptide), tirofiban (small molecule)
• Protease-activated-receptor-1 (PAR-1) antagonist:
  • Vorapaxar (Zontivity)
• Phosphodiesterase inhibitors (with secondary antiplatelet effect):
  • Dipyridamole (in fixed combination with aspirin as Aggrenox for secondary stroke prevention)
  • Cilostazol (for symptomatic peripheral arterial disease intermittent claudication)
• Adenosine reuptake inhibitor (largely retired): dipyridamole alone

The boundary of this category is "medicine that inhibits platelet activation, adhesion, or aggregation to prevent or treat arterial thrombosis." The anticoagulants (heparins, warfarin, DOACs) act on the coagulation cascade rather than on platelets and are collected separately; the two categories are often combined clinically (the "triple therapy" of aspirin + clopidogrel + warfarin or DOAC for atrial fibrillation with concurrent coronary stenting), but the medicines are pharmacologically distinct. The fibrinolytic medicines (alteplase, tenecteplase, streptokinase, reteplase) lyse already-formed thrombi rather than preventing their formation and are listed under a separate category. The thrombopoietin receptor agonists (romiplostim, eltrombopag, avatrombopag) increase platelet production rather than inhibiting platelet function and are not in this category. Selected NSAIDs other than aspirin have some antiplatelet effect at higher doses but are not used clinically for this purpose and are not collected here.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.