Category:Antiplatelet agents: Difference between revisions
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The category begins with aspirin. The antiplatelet effect of acetylsalicylic acid, taken since 1899 as an analgesic, antipyretic, and anti-inflammatory, was identified by [[wikipedia:Harvey J. Weiss|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;<ref name="weiss1967">Weiss HJ, Aledort LM, Kochwa S. The effect of salicylates on the hemostatic properties of platelets in man. ''Journal of Clinical Investigation''. 1968 Sep;47(9):2169-2180. PMID 4232539.</ref> the British pharmacologist [[wikipedia:John Vane|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.<ref name="isis2_1988">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. ''Lancet''. 1988 Aug 13;2(8607):349-360. PMID 2899772.</ref> | The category begins with aspirin. The antiplatelet effect of acetylsalicylic acid, taken since 1899 as an analgesic, antipyretic, and anti-inflammatory, was identified by [[wikipedia:Harvey J. Weiss|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;<ref name="weiss1967">Weiss HJ, Aledort LM, Kochwa S. The effect of salicylates on the hemostatic properties of platelets in man. ''Journal of Clinical Investigation''. 1968 Sep;47(9):2169-2180. PMID 4232539.</ref> the British pharmacologist [[wikipedia:John Vane|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.<ref name="isis2_1988">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. ''Lancet''. 1988 Aug 13;2(8607):349-360. PMID 2899772.</ref> | ||
The second class of antiplatelet was the [[:Category:Thienopyridines|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. [[wikipedia:Clopidogrel|Clopidogrel]] (Sanofi/BMS, 1997), a closely related | The second class of antiplatelet was the [[:Category:Thienopyridines|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. [[wikipedia:Clopidogrel|Clopidogrel]] (Sanofi/BMS, 1997), a closely related compound 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.<ref name="cure2001">CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. ''New England Journal of Medicine''. 2001 Aug 16;345(7):494-502. PMID 11519503.</ref> [[wikipedia:Prasugrel|Prasugrel]] (Daiichi Sankyo/Lilly, 2009) and [[wikipedia:Ticagrelor|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 [[wikipedia:Abciximab|abciximab]] (Centocor, 1994), and the small-molecule inhibitors [[wikipedia:Eptifibatide|eptifibatide]] (1998) and [[wikipedia:Tirofiban|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. | 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 [[wikipedia:Abciximab|abciximab]] (Centocor, 1994), and the small-molecule inhibitors [[wikipedia:Eptifibatide|eptifibatide]] (1998) and [[wikipedia:Tirofiban|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. | ||
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* '''Cyclooxygenase-1 inhibitors''': [[Aspirin|aspirin]] (low-dose for antiplatelet effect, 75-100 mg daily) | * '''Cyclooxygenase-1 inhibitors''': [[Aspirin|aspirin]] (low-dose for antiplatelet effect, 75-100 mg daily) | ||
* '''[[:Category:P2Y12_inhibitors|P2Y12 inhibitors]]''' (ADP-receptor antagonists): | * '''[[:Category:P2Y12_inhibitors|P2Y12 inhibitors]]''' (ADP-receptor antagonists): | ||
** [[:Category:Thienopyridines|Thienopyridine]] | ** [[:Category:Thienopyridines|Thienopyridine]] precursors (irreversible, require hepatic activation): [[wikipedia:Clopidogrel|clopidogrel]] (Plavix), [[wikipedia:Prasugrel|prasugrel]] (Effient), [[wikipedia:Ticlopidine|ticlopidine]] (largely retired) | ||
** Non-thienopyridine direct-acting reversible: [[wikipedia:Ticagrelor|ticagrelor]] (Brilinta), [[wikipedia:Cangrelor|cangrelor]] (intravenous) | ** Non-thienopyridine direct-acting reversible: [[wikipedia:Ticagrelor|ticagrelor]] (Brilinta), [[wikipedia:Cangrelor|cangrelor]] (intravenous) | ||
* '''Glycoprotein IIb/IIIa receptor antagonists''' (intravenous, in-hospital use): | * '''Glycoprotein IIb/IIIa receptor antagonists''' (intravenous, in-hospital use): | ||