Ischemic heart disease and cerebrovascular disease remain major health problems with associated mortality and quality-of-life consequences. Antiplatelet agents, including thienopyridines and the new P2Y12 inhibitors, have been shown to improve survival in the secondary prevention setting. We review the available evidence on the effectiveness and safety of previous established as well as novel antithrombotic agents in the secondary prevention of cardiovascular disease with a special focus on cerebrovascular disease.
Lloyd-JonesDAdamsRCarnethonM. Heart disease and stroke statistics-2009 update: a report from the American heart association statistics committee and stroke statistics subcommittee. Circulation. 2009;119(3):e21–e181.
2.
DuncanPWZorowitzRBatesB. Management of adult stroke rehabilitation care: a clinical practice guideline. Stroke. 2005;36(9):e100–e143.
3.
RogerVLGoAS Lloyd-JonesDM. Heart Disease and Stroke Statistics-2012 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2012;125(1):e2–e220.
4.
HallMJLevantSDeFrancesCJ. Hospitalization for stroke in U.S. hospitals, 1989-2009. NCHS Data Brief. 2012;(95):1–8.
5.
LiaoJK. Secondary prevention of stroke and transient Ischemic attack is more platelet inhibition the answer?Circulation. 2007;115(12):1615–1621.
6.
WhiteHBoden-AlbalaBWangC. Ischemic stroke subtype incidence among whites, blacks, and hispanics: the Northern Manhattan study. Circulation. 2005;111(10):1327–1331.
7.
WittBJBrownRDJrJacobsenSJWestonSAYawnBPRogerVL. A community-based study of stroke incidence after myocardial infarction. Ann Intern Med. 2005;143(11):785–792.
8.
GorelickPB. North American perspective of antiplatelet agents. Adv Neurol. 2003;92:281–291.
9.
VaneJRBottingRM. The mechanism of action of aspirin. Thromb Res. 2003;110(5-6):255–258.
10.
HarkerLAKadatzRA. Mechanism of action of dipyridamole. Thromb Res Suppl. 1983;4:39–46.
11.
HolmesMVPerelPShahTHingoraniADCasasJP. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. 2011;306(24):2704–2714.
12.
MatsagasMJagroopIAGeroulakosGMikhailidisDP. The effect of a loading dose (300 mg) of clopidogrel on platelet function in patients with peripheral arterial disease. Clin Appl Thromb Hemost. 2003;9(2):115–120.
13.
PetersenKU. Relevance of metabolic activation pathways: the example of clopidogrel and prasugrel. Arzneimittelforschung. 2009;59(5):213–227.
14.
HerbertJMSaviP. P2Y12, a new platelet ADP receptor, target of clopidogrel. Semin Vasc Med. 2003;3(2):113–122.
15.
HelftGOsendeJIWorthleySG. Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin. Arterioscler Thromb Vasc Biol. 2000;20(10):2316–2321.
16.
Van GiezenJJHumphriesRG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost. 2005;31(2):195–204.
17.
KowalczykMBanachMMikhailidisDPHannamSRyszJ. Ticagrelor-a new platelet aggregation inhibitor in patients with acute coronary syndromes. An improvement of other inhibitors?Med Sci Monit. 2009;15(12):MS24–MS30.
18.
HustedSEmanuelssonHHeptinstallSSandsetPMWickensMPetersG. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27(9):1038–1047.
19.
GurbelPABlidenKPButlerK. Randomised double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009;120(25):2577–2585.
20.
FerreiroJLUenoMAngiolilloDJ. Cangrelor: a review on its mechanism of action and clinical development. Expert Rev Cardiovasc Ther. 2009;7(10):1195–1201.
21.
WongPCCrainEJXinB. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost. 2008;6(5):820–829.
22.
MegaJLBraunwaldEMohanaveluS. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009;374(9683):29–38.
23.
ChackalamannilSWangYGreenleeWY. Discovery of a novel, orally active himbacine- based Thrombin receptor antagonist (Sch 530348) with potent antiplatelet activity. J Medicinal Chem. 2008;51(11):3061–3064.
24.
YusufSZhaoFMehtaSR. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494–502.
25.
SteinhublSRBergerPBMannJT 3rd. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomised controlled trial. JAMA. 2002;288(19):2411–2420.
26.
ChenZMJiangLXChenYP. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366(9497):1607–1621.
27.
SabatineMSCannonCPGibsonCM. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352(12):1179–1189.
28.
SabatineMSCannonCPGibsonCM. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA. 2005;294(10):1224–1232.
29.
WiviottSDBraunwaldEMcCabeCH. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001–2015.
30.
RoeMTArmstrongPWFoxKA. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367(14):1297–1309.
31.
CannonCPHarringtonRAJamesS. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet. 2010;375(9711):283–293.
32.
WallentinLBeckerRCBudajA. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–1057.
33.
HarringtonRAStoneGWMcNultyS. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med. 2009;361(24):2318–2329.
34.
BhattDLLincoffAMGibsonCM. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med. 2009;361(24):2330–2341.
35.
MehtaSRTanguayJFEikelboomJW. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet. 2010;376(9748):1233–1243.
36.
AlexanderJHLopesRDJamesS. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365(8):699–708.
37.
MegaJLBraunwaldEWivviottSD. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9–19.
38.
TricociPHuangZHeldC. Thrombin-Receptor Antagonist Vorapaxar in acute coronary syndromes. N Engl J Med. 2012;366(1):20–33.
39.
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE steering committee. Lancet. 1996;348(9038):1329–1339.
40.
DienerHCBogousslavskyJBrassLM. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331–337.
41.
DienerHCBogousslavskyJBrassLM. Management of atherothrombosis with clopidogrel in high risk patients with recent ischaemic stroke or transient ischaemic attack (MATCH): study design and baseline data. Cerebrovasc. Dis. 2004;17(2-3):253–261.
42.
BhattDLFoxKAHackeW. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16):1706–1717.
43.
BhattDLFlatherMDHackeW. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol. 2007;49(19):1982–1988.
44.
HartRGBhattDLHackeW. Clopidogrel and aspirin versus aspirin alone for the prevention of stroke in patients with a history of atrial fibrillation: subgroup analysis of the CHARISMA randomized trial. Cerebrovasc Dis. 2008;25(4):344–347.
45.
HankeyGJJohnstonSCEastonJD. Effect of clopidogrel plus ASA vs ASA early after TIA and ischaemic stroke: a substudy of the CHARISMA trial. Int J Stroke. 2011;6(1):3–9.
46.
BenaventeORHartRGMcClureLA. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke (SPS3 trial)N Engl J Med. 2012;367(9):817–825.
47.
KennedyJHillMDRyckborstKJ. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007;6(11):961–969.
48.
WangYJohnstonSC. Rationale and design of a randomised, double-blind trial comparing the effects of a 3-month clopidogrel-aspirin regimen versus aspirin alone for the treatment of high-risk patients with acute nondisabling cerebrovascular event. Am Heart J. 2010;160(3):380–386.
DienerHCSaccoRYusufSSteering Commitee, PRoFESS Study Group. Rationale, design and baseline data of a randomised, double-blind, controlled trial comparing two antithrombotic regimens (a fixed-dose combination of extended-release dipyridamole plus ASA with clopidogrel) and telmisartan versus placebo in patients with strokes: the prevention regimen for effectively avoiding second strokes trial (PRoFESS). Cerebrovasc Dis. 2007;23(5-6):368–380.
51.
MorrowDABraunwaldEBonacaMP. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366(15):1404–1413.
52.
GageBFWatermanADShannonWBoechlerMRichMWRadfordMJ. Validation of clinical classification schemes for predicting stroke: results from the national registry of atrial fibrillation. JAMA. 2001;285(22):2864–2870.
53.
ConnollySPogueJHartR. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367(9526):1903–1912.
54.
ConnollySPogueJHartR. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360(20):2066–2078.
55.
SaccoRLDienerHCYusufS. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359(12):1238–1251.
56.
KentDMThalerDE. Stroke prevention—Insights from incoherence. N Engl J Med. 2008;359(12):1287–1289.
57.
JohnsonESLanesSFWentworthCEIIISatterfieldMHAbeleBLDickerLW. A metaregression analysis of the dose-response effect of aspirin on stroke. Arch Intern Med. 1999;159(11):1248–1253.
58.
BhattDLCryerBLContantCF. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363(20):1909–1917.
59.
MitsiosJVPapathanasiouAIElisafMGoudevenosJATselepisAD. The inhibitory potency of clopidogrel on ADP-induced platelet activation is not attenuated when it is co-administered with atorvastatin (20 mg/day) for 5 weeks in patients with acute coronary syndromes. Platelets. 2005;16(5):287–92.
60.
GoengBKJeongKKParkS. Effect of atorvastatin and clopidogrel co-administration after coronary stenting in korean patients with stable angina. Korean Circ J. 2011;41(1):28–33.
61.
AmarencoPBogousslavskyJCallahanA3rd. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549–559.
62.
KimSDKangWLeeHW. Bioequivalence and tolerability of two clopidogrel salt preparations, besylate and bisulfate: a randomised, open-label, crossover study in healthy Korean male subjects. Clin Ther. 2009;31(4):793–803.
63.
ParkJYKimKARyuJHLeeGHJeonSHKimJS. Pharmacokinetics and the antiplatelet effect of a new clopidogrel formulation, clopidogrel besylate, in healthy subjects. Int J Clin Pharmacol Ther. 2010;48(4):259–269.
64.
TsoumaniMEKalantziKDimitriouAANtalasIVGoudevenosIATselepisAD. Antiplatelet efficacy of long-term treatment with clopidogrel besylate in patients with a history of acute coronary syndrome: comparison with clopidogrel hydrogen sulfate. Angiology. 2012;63(7):547–551.
65.
TsoumaniMEKalantziKDimitriouAANtalasIVGoudevenosIATselepisAD. Effect of clopidogrel besylate on platelet reactivity in patients with acute coronary syndromes. comparison with clopidogrel hydrogen sulfate. Exp Opin Pharmacother. 2012;13(2):149–158.
66.
HackeW. From CURE to MATCH: ADP receptor antagonists as the treatment of choice for high-risk atherothrombotic patients. Cerebrovasc Dis. 2002;13(suppl 1):22–26.
67.
Holloway RG VickreyBG Benesch CHinchey JA BieberJ, National Expert Stroke Panel. Development of performance measures for acute ischemic stroke. Stroke. 2001;32(9):2058–2074.
ZanchettiAHanssonLDahloB. Benefit and harm of low-dose aspirin in well treated hypertensives at different baseline cardiovascular risk. J Hypertens. 2002;20(11):2301–2307.
71.
ZanchettiA.Aspirin and antiplatelet drugs in the prevention of cardiovascular complications in diabetes. In: MorgensenCE, ed. Pharmacotherapy of Diabetes: New Developments. New York: Springer. 2007; 211–218.
72.
LipGYFelmedenDCDwivediG. Antiplatelet agents and anticoagulants for hypertension. Cochrane Database Syst Rev. 2011;(12):CD003186. doi: 10.1002/14651858.
73.
GkaliagkousiEPassacqualeGDoumaSZamboulisCFerroA. Platelet activation in essential hypertension: implications for antiplatelet treatment. Am J Hypertens. 2010;23(3):229–236.
74.
DucrocqGAmarencoPLabreucheJ. A History of stroke/transient ischemic attack indicates high risks of cardiovascular event and hemorrhagic stroke in patients with coronary artery disease. Circulation. 2013;127(6):730–738.
75.
BarnettHJEliasziwMMeldrumH. Drugs and surgery in the prevention of ischemic stroke. N Engl J Med. 1995;332(4):238–248.
76.
ColletJPMontalescotG. Any room left for new antiplatelet agents in acute coronary syndrome?Eur Heart J. 2013;34(23):1699–1701.
77.
KeiAAFlorentinMMikhailidisDPElisafMSLiberopoulosEN. Antiplatelet drugs: what comes next?Clin Appl Thromb Hemost. 2011;17(1):9–26.
78.
FurieKLKasnerSEAdamsRJ. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack, American stroke association. Stroke.2011;42(1):227–276.
79.
JauchECJeffreyLSaverJL. Guidelines for the early management of patients with acute ischemic stroke. Stroke. 2013;44(3):870–947.