Controversies in Antiplatelet Therapy for Patients With Cardiovascular Disease
2005; Lippincott Williams & Wilkins; Volume: 111; Issue: 17 Linguagem: Inglês
10.1161/01.cir.0000157158.63751.b2
ISSN1524-4539
Autores Tópico(s)Atrial Fibrillation Management and Outcomes
ResumoHomeCirculationVol. 111, No. 17Controversies in Antiplatelet Therapy for Patients With Cardiovascular Disease Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBControversies in Antiplatelet Therapy for Patients With Cardiovascular Disease Eric R. Bates and Wei C. Lau Eric R. BatesEric R. Bates From the Division of Cardiovascular Medicine (E.R.B.), Department of Internal Medicine, and the Department of Anesthesiology (W.C.L.), University of Michigan, Ann Arbor, Mich. and Wei C. LauWei C. Lau From the Division of Cardiovascular Medicine (E.R.B.), Department of Internal Medicine, and the Department of Anesthesiology (W.C.L.), University of Michigan, Ann Arbor, Mich. Originally published3 May 2005https://doi.org/10.1161/01.CIR.0000157158.63751.B2Circulation. 2005;111:e267–e271Case presentation: An asymptomatic man (J.D.) is referred for a cardiovascular evaluation. He has a strong family history of coronary artery disease and has received more than 10 years of treatment for hypertension and dyslipidemia. Past medical history is significant for symptomatic degenerative joint disease. Medications include hydrochlorothiazide, lisinopril, atorvastatin, and celecoxib. How should he be counseled about antiplatelet therapy?Aspirin for Primary PreventionAcetylsalicylic acid (aspirin) has been commercially available as an analgesic and antiinflammatory agent for more than a century. In recent years, the demonstrated ability of aspirin to inhibit platelet aggregation and prevent thrombotic cardiovascular events has made it the most important cardiovascular medication from both risk-benefit and cost-benefit standpoints. Aspirin and other nonsteroidal antiinflammatory agents (NSAIDs) inhibit arachidonic acid metabolism by inactivating the cyclooxygenase (COX) enzyme system.1 Normally, arachidonic acid gains access to its catalytic site in the platelet through a hydrophobic channel within COX-1 (Figure 1A) and is ultimately converted to thromboxane A2 (TxA2), which promotes vasoconstriction and platelet aggregation (Figure 2). Aspirin acts by irreversibly acetylating a serine residue at position 530 within the channel, blocking access of arachidonic acid to its catalytic site, and preventing metabolism of arachidonic acid for the lifetime of the platelet (Figure 1B). Other NSAIDs are reversible, competitive inhibitors of the catalytic site, inhibiting platelet aggregation only during part of the dosing interval. No data exist to suggest that NSAIDs, other than aspirin, reduce cardiovascular events. Download figureDownload PowerPointFigure 1. Effect of aspirin alone and ibuprofen plus aspirin on platelet COX-1. A, Arachidonic acid substrate binds to its catalytic site within hydrophobic channel in COX-1 enzyme. B, Aspirin blocks access of arachidonic acid to its catalytic site by irreversibly acetylating serine residue at position 530 (depicted as 529) in COX-1. C, Prior occupancy of catalytic site by ibuprofen prevents aspirin from gaining access to its binding site.1 Copyright © 2001 Massachusetts Medical Society. All rights reserved.Download figureDownload PowerPointFigure 2. Effects of NSAIDs on platelets and vascular endothelial cells. Balance between thromboxane and prostacyclin is important in thrombosis. COX-1 inhibitors decrease thromboxane production more effectively than prostacyclin production, tipping the balance away from thrombosis. In contrast, COX-2 inhibitors inhibit only prostacyclin production, decreasing inflammation but tipping the balance toward thrombosis. ASA indicates aspirin; Coxibs, COX inhibitors.The use of aspirin for primary prevention remains controversial in low-risk patients because the risk for gastrointestinal bleeding and hemorrhagic stroke may outweigh the benefit of preventing rare cardiovascular events.2 However, in patients whose estimated risk for an event is >1%/year, as measured by the Framingham Risk Score3 or a similar risk algorithm, aspirin therapy for cardioprotection is a reasonable recommendation.2 Risk factors for J.D. include age, gender, family history, hypertension, and dyslipidemia. His risk for a cardiovascular event is increased by any risk algorithm, and he would be a good candidate for aspirin therapy to reduce the risk of a first myocardial infarction (MI).COX-2 Inhibitors in Patients at Risk for Cardiovascular DiseaseWhereas COX-1 is expressed by many cells and is routinely involved in maintaining cellular functions, COX-2 is expressed only in response to inflammatory stimuli, mediates a significant component of the inflammatory response, and is present in only a small fraction of platelets. COX-2 inhibitors have become a very popular class of drugs for the treatment of arthritis pain because they do not have significant gastric toxicity, a complication associated with inhibition of COX-1. No data exist to suggest that they offer superior pain relief compared with NSAIDs, and like NSAIDS, they can cause salt and water retention, renal insufficiency, and worsening of hypertension. They are convenient, with once- or twice-daily dosing, but they are also expensive, costing $2 to $3 per tablet. COX-2 inhibitors are not an acceptable substitute for aspirin in patients who need antiplatelet therapy for cardioprotection because they do not inhibit TxA2 production. Conversely, their use in patients who require aspirin therapy offers no advantage over less expensive NSAIDs because they do not offer a safety advantage.By selectively decreasing prostacyclin (PGI2) production without inhibiting TxA2 production (Figure 2), COX-2 inhibitors theoretically might decrease the vasodilatory and platelet antiaggregatory effects of PGI2 without inhibiting the vasoconstrictor and platelet aggregatory effects of TxA2. The concern that one COX-2 inhibitor, rofecoxib, could increase the risk of thrombotic cardiovascular events has existed for several years.4 Rofecoxib was withdrawn from the market after the 25-mg dose was found to double the risk of MI or stroke compared with placebo (3.5% versus 1.9%) after 18 months of therapy in a randomized trial that tested the utility of rofecoxib in preventing recurrent colorectal polyps in patients with no significant history for cardiovascular disease. The risk could be greater in patients at risk for or with known atherosclerotic vascular disease. Although the other COX-2 drugs on the market, celecoxib and valdecoxib, have not yet been shown to increase cardiovascular events, neither one has been tested long-term in patients with cardiovascular disease. The cardiovascular question about the available drugs in this class is whether their antiinflammatory effects balance their potential prothrombotic effects. Their prescription to patients at risk for cardiovascular events probably should be avoided until their safety can be demonstrated.A better strategy for treating patients with both arthritis and risk for cardiovascular events would be to first try acetaminophen, up to 4 g/d. If acetaminophen is not successful, then naproxen may be prescribed. If the patient is at increased risk for a gastrointestinal event caused by aspirin or naproxen (eg, age >60 years old, history of gastrointestinal or duodenal ulcer, taking coumadin), then a gastroprotective agent (a proton pump inhibitor or misoprostol) can be added. This information was discussed with J.D., and he was advised to stop taking celecoxib.The Aspirin-Ibuprofen Drug-Drug InteractionThe omission of ibuprofen as an acceptable substitute for COX-2 inhibitor therapy in patients taking aspirin for cardioprotection should be noted. Aspirin given 2 hours before a daily dose of ibuprofen successfully inhibits platelet aggregation1; however, ibuprofen administered 3 times per day competitively prevents aspirin from accessing its target serine and inhibiting platelet aggregation (Figure 1C). Some post hoc analyses5–7 suggested that patients taking both aspirin and ibuprofen had more cardiovascular events than patients taking either drug alone, although others found no clinical risk.8,9 J.D. was advised that ibuprofen could be taken episodically after his daily aspirin dose, but that it should not be taken daily in multiple doses to treat arthritis pain because of his need for aspirin cardioprotection.The Aspirin-ACE Inhibitor Drug-Drug InteractionThe inhibition of COX-1 by aspirin in the endothelial cell also inhibits the synthesis of PGI2 (Figure 2). ACE inhibitors (ACEIs) increase prostaglandin production by inhibiting the breakdown of bradykinin. Coadministration of these agents could reduce the prostaglandin-mediated decrease in arterial pressure associated with ACEIs and potentiate depression of renal function by decreasing synthesis of renal vasodilatory prostaglandins. Although some retrospective analyses have suggested that coadministration of these drugs decreases the mortality benefit associated with ACEI therapy in patients with heart failure or ischemic heart disease, other studies have suggested that a decrease in mortality does not occur.10 Because aspirin 81 mg/d has the same efficacy as 325 mg/d, with half the bleeding risk,11 J.D. was advised to take the lower aspirin dose with the additional theoretical possibility that any interaction with his ACEI would be decreased.Case presentation, continued: Unfortunately, J.D. presented 6 months after initial evaluation to his community hospital with an anterior ST-elevation MI and was successfully treated with fibrinolytic therapy 2.5 hours after symptom onset. He had no complications, and a submaximal exercise treadmill test was negative for ischemia; he was discharged from the hospital and referred to a cardiac rehabilitation program.Aspirin "Resistance"One definition of the term "aspirin resistance" is the occurrence of cardiovascular events despite aspirin therapy. This term is imprecise, because 75% of cardiovascular events are not prevented by aspirin,12 and no pharmacological intervention is perfect in preventing adverse outcomes. These events might better be characterized as treatment failures rather than drug resistance due to failure of the drug to hit its pharmacological target or alter the target.13 However, measurements of bleeding time, platelet activation, platelet aggregation, and urinary thromboxane B2 metabolites confirm variability in patient responses to aspirin, and some patients are nonresponders. Moreover, small observational studies suggest that nonresponders have increased cardiovascular events compared with responders,14–17 and the occurrence of a cardiovascular event while taking aspirin is designated as a risk point in the TIMI (Thrombolysis In Myocardial Infarction) risk score for unstable angina/non–ST-elevation MI or ST-elevation MI.19,20 Until a biochemical mechanism for aspirin resistance can be defined and measured with a laboratory test that can be linked to clinical outcomes in randomized clinical trials, the concept of aspirin resistance will remain controversial and of unknown clinical significance. Because of the epidemiological evidence supporting the benefit of aspirin cardioprotection and the absence of data on the benefit of thienopyridines after ST-elevation MI, J.D. was instructed to continue taking low-dose aspirin. A β-blocker was added to his medications, his atorvastatin dose was increased to 80 mg/d, and his lisinopril dose was also increased.Case presentation, continued: J.D. developed reproducible exertional chest discomfort during cardiac rehabilitation. A nuclear imaging study demonstrated a large anterior perfusion defect with significant redistribution. Cardiac catheterization was performed, single-vessel disease with a high-grade stenosis in the proximal left anterior descending artery was demonstrated, and the stenosis was successfully treated with implantation of a coronary stent.Clopidogrel "Resistance"The combination of clopidogrel and aspirin therapy (dual-antiplatelet therapy) has been shown to decrease both subacute stent thrombosis and recurrent ischemic events after acute coronary syndromes21 and elective percutaneous coronary intervention.22 As with aspirin, variable platelet aggregation inhibition after clopidogrel occurs among individuals; nonresponders to clopidogrel have been identified.23,24 One major mechanism may be the failure of clopidogrel, a prodrug, to be metabolized to its active metabolite by hepatic cytochrome P450 (CYP) 3A4.24 Multiple other possible mechanisms include underdosing, impaired gastric absorption, ADP receptor P2Y12 polymorphisms, and intracellular signaling variability.25Increased rates of subacute stent thrombosis23 and recurrent ischemic events after primary PCI26 have been noted in clopidogrel nonresponders. However, further work is needed in defining clopidogrel "resistance," measuring it, and correlating it with adverse clinical events before it becomes clinically relevant. J.D. was advised to take clopidogrel 75 mg/d for 6 to 12 months to decrease his risk for subacute stent thrombosis and subsequent ischemic events.The Clopidogrel-Atorvastatin Drug-Drug InteractionClopidogrel and atorvastatin are competitive substrates for the CYP3A4 enzyme system.27,28 Because clopidogrel has low bioavailability and a lower affinity than atorvastatin for the substrate binding site, and because atorvastatin has a long half-life, atorvastatin competitively inhibits the ability of clopidogrel to be metabolized to its active metabolite in a dose-dependent manner (Figure 3).28 A loading dose of clopidogrel 600 mg overcomes this drug-drug interaction,29 but neither a 300-mg loading dose nor the 75-mg maintenance dose prevents higher doses of atorvastatin from decreasing the ability of clopidogrel to inhibit platelet aggregation.27 The reports suggesting an association between clinical events and aspirin resistance, aspirin drug-drug interactions, and clopidogrel resistance have been controversial. One report also has suggested that the clopidogrel-atorvastatin drug-drug interaction increases the occurrence of adverse events,30 although others have contested the clinical significance.31,32 Until a therapeutic mechanism other than inhibition of platelet aggregation can be proven to be important for antiplatelet agents, however, it appears logical to expect more clinical events in patients with less platelet inhibition. J.D. was advised to stop his high-dose atorvastatin and was given a prescription for pravastatin, because it is not metabolized by the liver and does not interfere with clopidogrel metabolism. Failure to reach his target LDL levels with pravastatin could be treated by the addition of ezetimibe or extended-release niacin, the substitution of rosuvastatin for pravastatin, or resumption of atorvastatin after clopidogrel is discontinued. Download figureDownload PowerPointFigure 3. Competition for cytochrome P450 (CYP) pathways increases potential for drug-drug interactions. Most common mechanism for drug-drug interaction is when 2 or more drugs ("substrates") using same CYP pathway are coadministered, which results in competition for elimination. This results in higher plasma levels of less-competitive agent, which increases potential for adverse drug reaction. With prodrug clopidogrel, failure to be activated because of competition for CYP 3A4 pathway with atorvastatin decreases plasma levels of active metabolite and inhibition of platelet aggregation.ConclusionsThe variable response of platelet aggregation to antiplatelet drugs appears to be a clinically important phenomenon. Clinically, it appears reasonable to avoid drug-drug interactions that might interfere with antiplatelet therapy cardioprotection. Eventually, it is likely that platelet function will be measured before and after the institution of antiplatelet therapy to prove efficacy, as is done with anticoagulation therapy with unfractionated heparin or warfarin, and that optional strategies will be developed for those with inadequate inhibition of platelet aggregation.FootnotesCorrespondence to Eric R. Bates, MD, B1 238 Taubman Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109. E-mail [email protected] References 1 Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, Fitzgerald GA. Cyclo-oxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001; 345: 1809–1817.CrossrefMedlineGoogle Scholar2 Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002; 136: 161–172.CrossrefMedlineGoogle Scholar3 Wilson PWF, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kanel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998; 97: 1837–1847.CrossrefMedlineGoogle Scholar4 Mukherjee D, Nissen SE, Topol EJ. Cardiovascular events and COX-2 inhibitors. JAMA. 2001; 286: 2808–2813.Google Scholar5 McDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet. 2003; 361: 573–574.CrossrefMedlineGoogle Scholar6 Kurth T, Glynn RJ, Walker AM, Chan KA, Buring JE, Hennekens CH, Graziano JM. Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal anti-inflammatory drugs. Circulation. 2003; 108: 1191–1195.LinkGoogle Scholar7 Kimmel SE, Berlin JA, Reilly M, Jaskowiac J, Kishel L, Chittams J, Strom BL. The effects of nonselective non-aspirin non-steroidal anti-inflammatory medications on the risk of nonfatal myocardial infarction and their interaction with aspirin. J Am Coll Cardiol. 2004; 43: 985–990.CrossrefMedlineGoogle Scholar8 Curtis J, Wang Y, Portnay EL, Masoudi FA, Havranek EP, Krumholz HM. Aspirin, ibuprofen, and mortality after myocardial infarction: retrospective cohort study. BMJ. 2003; 327: 1322–1323.CrossrefMedlineGoogle Scholar9 Garcia Rodriguez LA, Varas-Lorenzo C, Maguire A, Gonzalez-Perez A. Nonsteroidal antiinflammatory drugs and the risk of myocardial infarction in the general population. Circulation. 2004; 109: 3000–3006.LinkGoogle Scholar10 Teo KK, Yusuf S, Pfeffer M, Torp-Pedersen C, Kober L, Hall A, Pogue J, Latini R, Collins R. Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review. Lancet. 2002; 360: 1037–1043.CrossrefMedlineGoogle Scholar11 Anti Thrombotic Trialists' Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324: 71–86.CrossrefMedlineGoogle Scholar12 Hennekens CH, Schror K, Weisman S, FitzGerald GA. Terms and conditions: semantic complexity and aspirin resistance. Circulation. 2004; 110: 1706–1708.LinkGoogle Scholar13 Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance. Arterioscler Thromb Vasc Biol. 2004; 24: 1–8.LinkGoogle Scholar14 Grotemeyer KH, Scharafinski HW, Husstedt IW. Two-year follow-up of aspirin responder and aspirin non responder: a pilot-study including 180 post-stroke patients. Thromb Res. 1993; 71: 397–403.CrossrefMedlineGoogle Scholar15 Mueller MR, Salat R, Strangl P, Murabito M, Pulaki S, Boehm D, Koppensteiner R, Ergun E, Mittlboeck M, Schreiner W. Variable platelet response to low-dose ASA and the risk of limb deterioration in patients submitted to peripheral artery angioplasty. Thromb Haemost. 1997; 78: 1003–1007.CrossrefMedlineGoogle Scholar16 Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol. 2003; 41: 961–965.CrossrefMedlineGoogle Scholar17 Chen W-H, Lee P-Y, Ng W, Tse HF, Lau CP. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol. 2004; 43: 1122–1126.CrossrefMedlineGoogle Scholar18 Antman EM, Coh M, Bernink PJLM, McCabe DH, Horacek T, Pappuchis G, Mautner B, Corbalan R, Radley D, Braunwald E. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000; 284: 835–842.CrossrefMedlineGoogle Scholar19 Morrow DA, Antman EM, Charlesworth A, Cairns R, Murphy SA, deLemos JA, Giugliano RP, McCabe CH, Braunwald E. TIMI risk score for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation: an intravenous NPA for treatment of infarcting myocardium InTIME II trial substudy. Circulation. 2000; 102: 2031–2037.CrossrefMedlineGoogle Scholar20 The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-elevation [published correction appears in N Engl J Med. 2001;345:1506,1716]. N Engl J Med. 2001; 345: 494–502.CrossrefMedlineGoogle Scholar21 Steinhubl SR, Berger PB, Mann JTIII, Fry ET, DeLago A, Wilmer C, Topol EJ. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention; a randomized controlled trial. JAMA. 2002; 288: 2411–2420.CrossrefMedlineGoogle Scholar22 Muller I, Besta F, Schulz C, Massberg S, Schomig A, Gawaz M. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost. 2003; 89: 783–787.CrossrefMedlineGoogle Scholar23 Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville DG, Guyer KE, Tait AR, Bates ER. The contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation. 2004; 109: 166–171.LinkGoogle Scholar24 Wiviott SD, Antman EM. Clopidogrel resistance: a new chapter in a fast-moving story. Circulation. 2004; 109: 3064–3067.LinkGoogle Scholar25 Barragan P, Bouvier J-L, Roquebert P-O, Macaluso G, Commeau P, Comet B, Lafont A, Camoin L, Walter U, Eigenthaler M. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv. 2003; 59: 295–302.CrossrefMedlineGoogle Scholar26 Matetzky S, Shenkman B, Guetta V, Shecter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004; 109: 3171–3175.LinkGoogle Scholar27 Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation. 2003; 107: 32–37.LinkGoogle Scholar28 Clarke TA, Waskell LA. Clopidogrel is metabolized by human cytochrome P450 3A and inhibited by atorvastatin. Drug Metab Dispos. 2003; 31: 53–59.CrossrefMedlineGoogle Scholar29 Muller I, Besta F, Schulz C, Li Z, Massberg S, Gawaz M. Effects of statins on platelet inhibition by a high loading dose of clopidogrel. Circulation. 2003; 108: 2195–2197.LinkGoogle Scholar30 Brophy J, Costa V, Babapulle M. A pharmaco-epidemiological study of the interaction between atorvastatin and clopidogrel following percutaneous coronary interventions. J Am Coll Cardiol. 2004; 43: 50A. Abstract.Google Scholar31 Saw J, Steinhubl SR, Berger PB, Kereiakes DJ, Serebruany VL, Brennan D, Topol EJ. Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation. 2003; 108: 921–924.LinkGoogle Scholar32 Weinbergen H, Gitt AK, Schiele R, Juenger C, Heer T, Meisenzahl C, Limbourg P, Bossaller H, Senges J. Comparison of clinical benefits of clopidogrel therapy in patients with acute coronary syndromes taking atorvastatin versus other statin therapies. Am J Cardiol. 2003; 92: 285–288.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Us I, Zhuk S, Korolova D, Platonov O and Tsaryk Y (2022) Platelet hemostasis in the implementation of placental dysfunction, Reproductive health of woman, 10.30841/2708-8731.6.2022.267676:6, (6-12) Lin Y, Chen Y, Yuan J, Qin H, Dong S and Chen Q (2021) Impact of aspirin use on clinical outcomes in patients with vasospastic angina: a systematic review and meta-analysis, BMJ Open, 10.1136/bmjopen-2021-048719, 11:7, (e048719), Online publication date: 1-Jul-2021. Fujii N, Pastore O, McGarr G, Meade R, McNeely B, Nishiyasu T and Kenny G (2018) Cyclooxygenase-1 and -2 modulate sweating but not cutaneous vasodilation during exercise in the heat in young men, Physiological Reports, 10.14814/phy2.13844, 6:17, (e13844), Online publication date: 1-Sep-2018. Borges I, Sena I, Azevedo P, Andreotti J, Almeida V, Paiva A, Santos G, Guerra D, Prazeres P, Mesquita L, Silva L, Leonel C, Mintz A and Birbrair A (2017) Lung as a Niche for Hematopoietic Progenitors, Stem Cell Reviews and Reports, 10.1007/s12015-017-9747-z, 13:5, (567-574), Online publication date: 1-Oct-2017. Yazigi Junior J, dos Santos J, Xavier B, Fernandes M, Valente S and Leite V (2015) Quantification of platelets obtained by different centrifugation protocols in SHR rats, Revista Brasileira de Ortopedia (English Edition), 10.1016/j.rboe.2015.10.008, 50:6, (729-738), Online publication date: 1-Nov-2015. Yazigi Junior J, Gomes dos Santos J, Xavier B, Fernandes M, Valente S and Leite V (2015) Quantificação do número de plaquetas a partir de diferentes métodos de centrifugação em ratos da linhagem SHR, Revista Brasileira de Ortopedia, 10.1016/j.rbo.2015.04.018, 50:6, (729-738), Online publication date: 1-Nov-2015. Ghosh R, Alajbegovic A and Gomes A (2015) NSAIDs and Cardiovascular Diseases: Role of Reactive Oxygen Species, Oxidative Medicine and Cellular Longevity, 10.1155/2015/536962, 2015, (1-25), . Zhang P, Lin H, Qu C, Tang Y, Li N, Kai J, Shang G, Li B, Zhang L, Yan H, Liu P and Duan J (2015) Design, Synthesis, and In Vitro Antiplatelet Aggregation Activities of Ferulic Acid Derivatives , Journal of Chemistry, 10.1155/2015/376527, 2015, (1-7), . Geraldo R, Sathler P, Lourenço A, Saito M, Cabral L, Rampelotto P and Castro H (2014) Platelets: Still a Therapeutical Target for Haemostatic Disorders, International Journal of Molecular Sciences, 10.3390/ijms151017901, 15:10, (17901-17919) Picker S (2013) Platelet Function in Ischemic Heart Disease, Journal of Cardiovascular Pharmacology, 10.1097/FJC.0b013e318279b78a, 61:2, (166-174), Online publication date: 1-Feb-2013. Sachdeva R, Hughes B and Mehta J (2011) Statins in the Reduction of Cardiovascular Events Pharmaceutical Sciences Encyclopedia, 10.1002/9780470571224.pse450 Oqueli E, Hiscock M and Dick R (2007) Clopidogrel Resistance, Heart, Lung and Circulation, 10.1016/j.hlc.2007.03.012, 16, (S17-S28), Online publication date: 1-Jan-2007. DE Lorgeril M (2007) Essential Polyunsaturated Fatty Acids, Inflammation, Atherosclerosis and Cardiovascular Diseases Inflammation in the Pathogenesis of Chronic Diseases, 10.1007/1-4020-5688-5_13, (283-297), . Tantry U, Bliden K and Gurbel P (2006) Prasugrel, Expert Opinion on Investigational Drugs, 10.1517/13543784.15.12.1627, 15:12, (1627-1633), Online publication date: 1-Dec-2006. Jernberg T, Payne C, Winters K, Darstein C, Brandt J, Jakubowski J, Naganuma H, Siegbahn A and Wallentin L (2006) Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease, European Heart Journal, 10.1093/eurheartj/ehi877, 27:10, (1166-1173), Online publication date: 1-May-2006. May 3, 2005Vol 111, Issue 17 Advertisement Article InformationMetrics https://doi.org/10.1161/01.CIR.0000157158.63751.B2PMID: 15867186 Originally publishedMay 3, 2005 PDF download Advertisement SubjectsPharmacologyPlateletsThrombosis
Referência(s)