Aspirin Resistance: Focus on Clinical Endpoints : Journal of Cardiovascular Pharmacology (original) (raw)
INTRODUCTION
Antiplatelet therapy is a cornerstone of cardiovascular medicine. Clinical trials have shown the efficacy of aspirin in both the primary and secondary prevention of myocardial infarction, stroke, and cardiovascular death.1,2 In recent years, an increasing number of reports about aspirin resistance has led to a growing concern among clinicians and patients about the efficacy of aspirin treatment. Various studies have evaluated the antiplatelet effect of aspirin therapy and have reported the prevalence of aspirin resistance to be between 0.4% to 35%.3,4 However, these studies involved various doses of aspirin and methods to assess aspirin response.4 There is increasing evidence that these methods might not be comparable with each other.5,6 No standardized or widely accepted definition of aspirin resistance exists3,4; therefore, specific treatment recommendations for patients who exhibit high platelet reactivity during aspirin therapy or who have poor platelet inhibition by aspirin are not established.7 On the other hand, 2 recent meta-analyses showed the association between laboratory aspirin resistance and poor clinical outcome.8,9
METHODS
We searched PubMed, MEDLINE, and the Cochrane Library to March 12, 2008. We used these search items in the following combinations: aspirin, acetylsalicylic acid, failure, resistance, platelet aggregation, platelet activation, clinical outcome, hospitalisation, acute coronary syndrome, myocardial infarction, unstable angina, stable angina, peripheral artery disease, TIA, and stroke. After reviewing the abstracts, we obtained and reviewed the full text and reference lists of relevant articles. We included articles that addressed aspirin resistance and nonresponsiveness and its diagnosis, clinical outcome, and treatment. We collected the remaining articles based on the used laboratory methods.
PLATELET ADHESION, ACTIVATION, AGGREGATION, AND THE ANTIPLATELET EFFECT OF ASPIRIN
When the intima of a blood vessel is disrupted, as happens after a cut or the rupture of an atherosclerotic plaque, subendothelial collagen and von Willebrand factor are exposed to circulating blood. Platelets in the blood adhere to subendothelial collagen and von Willebrand factor through their glycoprotein Ia/IIa and Ib/V/IX receptors.4,10-12 Platelet adhesion stimulates platelet activation, which leads to a change in their shape and the release of bound calcium within the platelet.4,13 The increased concentration of free ionic calcium within the platelet has several consequences. First, it induces a conformational change in the platelet glycoprotein IIb/IIIa receptors on the surface of platelets so that they can bind adhesive proteins in the circulation, such as fibrinogen (Figure 1). Second, it catalyzes the release of active molecules (eg, ADP) from platelet granules into the circulation, where they can bind to receptors (eg, ADP) on the surface of adjacent platelets and trigger their activation. Third, it promotes the action of phospholipase A2 to produce arachidonic acid.12-15 Arachidonic acid in platelets is converted to thromboxane A2 in a reaction that is catalyzed by the enzymes cyclooxygenase 1 (to form prostaglandin G2/ H2) and thromboxane synthase (to form thromboxane A2). Thromboxane A2 increases the expression of fibrinogen receptors on the platelet's membrane and is released into the circulation, where it binds to thromboxane receptors on the surface of adjacent platelets to trigger their activation. Thromboxane A2 also acts synergistically with other products released by activated platelets (eg, ADP, fibrinogen, factor V) to augment platelet activation. Further, thromboxane A2 is a potent vasoconstrictor.4,12,15
Platelet adhesion, activation, and aggregation.
Aspirin (acetylsalicylic acid) reduces the activation of platelets by irreversibly acetylating cyclooxygenase-1 (COX-1) and thereby reduces thromboxane A2 produced by platelets.4,16 The inhibition of COX-1 is rapid, saturable at low doses (ie, dose-independent), irreversible, and permanent for the life of the platelet, because platelets lack the biosynthetic machinery to synthesize new protein. After a single 325-mg dose of aspirin, platelet COX-1 activity recovers by about 10% per day due to new platelet formation.4,16 Once-daily, low-dose aspirin (0·45 mg/kg, approximately 30 mg) suppresses serum thromboxane B2 formation (a stable metabolite of thromboxane A2) by at least 95% within about 5 days, and this level of inhibition is maintained with long-term daily administration.4,13-15 Aspirin also has dose-dependent antithrombotic effects on platelet function and blood coagulation that are unrelated to its ability to inhibit platelet COX-1.5 However, these mechanisms have not been correlated with known molecular mechanisms and are believed to be much less important than inhibition of platelet COX-1.4,10,12,16
THE DEFINITION OF ASPIRIN RESISTANCE
There is no generally accepted definition of aspirin resistance. The term has been used in a clinical and laboratory context. Clinical aspirin resistance has been used to refer to the inability of aspirin to protect individuals from cardiovascular thrombotic events such as acute myocardial infarction. However, many cardiovascular events that occur in patients treated with aspirin may not be preventable by aspirin. Furthermore, the diagnosis of clinical resistance can only be made in retrospect because an ischemic event must occur before a diagnosis of clinical resistance can be considered. Laboratory aspirin resistance refers to the lack of an anticipated effect of aspirin on a laboratory measure of its antiplatelet effect that is associated with a higher rate of future cardiovascular events.4
LABORATORY DETECTION OF ASPIRIN RESISTANCE AND CLINICAL OUTCOME
Thromboxane A2 Production
Serum thromboxane B2 (TxB2) reflects the total capacity of platelets to synthesize thromboxane A2, of which it is a stable metabolite, and is therefore the most specific test to measure the pharmacological effect of aspirin. The ability of platelets to synthesize TxB2 after in vitro stimulation with an agonist, such as collagen, can also be considered a specific test for measuring the effects of aspirin, albeit probably less sensitive and more time consuming than serum TxB2.4,10
The urinary levels of the TxB2 metabolite, 11-dehydrothromboxane B2, represent a time-integrated index of TxA2 biosynthesis in vivo. Because it is not formed in the kidney, detection of this TxA2 metabolite in the urine reflects systemic TxA2 formation, which largely, although not exclusively, occurs in the platelets. It has been calculated that about 30% of the urinary metabolite derives from extra-platelet sources; however, in pathological conditions such as in inflammatory diseases, the contribution of extra-platelet sources may increase. Therefore, the method is not highly specific for monitoring the effects of aspirin on platelet COX-1.12,17
Clinical Studies Based on Thromboxane A2 Production
We found 5 studies in which aspirin resistance was detected by this method.17-21 The definition of resistance was based on the thromboxane levels (compared to healthy volunteers, or patients were divided into groups depending on their thromboxane levels). Two studies found no association between aspirin resistance and poor clinical outcome (Table 1).
Clinical Studies Based on Thromboxane Measurements
Optical Aggregometry
Light or optical transmission aggregometry measures the increase in light transmission through a platelet suspension that occurs when platelets aggregate in response to an agonist. It is not ideal for testing platelet sensitivity to aspirin or thienopyridines for several reasons.4,10 First, it is time-consuming and should be performed in specialized laboratories only. Second, many preanalytical and analytical variables affect the results; even when all of them are controlled for, the accuracy and reproducibility of the technique are very poor. Third, the results obtained within 1 laboratory can hardly be compared with those obtained in a different laboratory because of lack of standardization; therefore, any attempt to define universal cutoff values of platelet aggregation to identify nonresponders to antiplatelet therapies would be pointless. Fourth, depending on the type and concentration of agonist used and the type of anticoagulant used for blood collection, the aggregation response is only partially and variably modulated by TxA2, synthesized from arachidonic acid in the platelet membrane, or ADP, released from platelet granules. Even when the 2 most specific platelet agonists are used, arachidonic acid for monitoring aspirin, and ADP for monitoring thienopyridines, the results obtained with this technique may overestimate the incidence of resistance to antiplatelet agents.12
Clinical Studies Based on Optical Aggregometry
We found 11 studies mainly based on optical aggregometry.22-32 The definition of resistance was based on platelet response to different agonsits (compared to healthy volunteers or event-free included vascular patients or depending on the difference between the pretreated and the treated stage). Four studies found no association between aspirin resistance and poor clinical outcome. All details can be seen in Table 2.
Clinical Studies Based on Optical Aggregometry
The PFA-100 System
The PFA-100 could be regarded as an in vitro bleeding time recorder.4,33 It consists of an artificial vessel built up by a sample reservoir, a capillary, and a biologically active membrane with a central aperture coated with collagen plus ADP or collagen plus epinephrine. The application of a constant negative pressure aspirates the anticoagulated blood of the sample from the reservoir through the capillary (mimicking the resistance of a small artery) and the aperture (mimicking high shear in the injured part of the vessel wall). A platelet plug forms that gradually occludes the aperture. Consequently, the blood flow through the aperture gradually decreases and ultimately stops. The time taken to interrupt blood flow-closure time is recorded.
The system is very easy to use, automated, quick, and requires a small volume of whole blood. It is sensitive to von Willebrand disease and to severe abnormalities of platelet function.10,12 In contrast, its sensitivity to mild/moderate, inherited, and drug-induced defects of platelet function is low: closure times (CT) of the C-EPI cartridge may be prolonged in some but not all patients on aspirin treatment, whereas variable but often normal CT have been observed on both C-ADP and C-EPI cartridges in samples from patients receiving clopidogrel therapy.4,10,12 The low sensitivity of the method to mild abnormalities of platelet function can be accounted for by the fact that it is sensitive to many variables, including platelet count, red blood cells, platelet reactivity to collagen and, above all, plasma VWF, the effects of which on platelet aggregate formation can easily outweigh the effects of mild inhibition of platelet function.4,10,12
Clinical Studies Based on the PFA-100 System
We found 15 studies mainly based on the PFA-100 system.34-48 Only 4 studies found no association between aspirin resistance and poor clinical outcome. The definition of resistance is based on the closure times (see above) and is laboratory-dependent. All details can be seen in Table 3.
Clinical Studies Based on the PFA 100 System
(continued) Clinical Studies Based on the PFA 100 System
Impedance Aggregometry
Impedance aggregometry measures the change in electrical impedance between 2 electrodes when platelets are aggregated by an agonist. The method is similar to light or optical aggregometry except that it can be done in whole blood, thus obviating the need for preparation of a platelet suspension. Impedance aggregometry can also be done in thrombocytopenic patients.4,49
Clinical Studies Based on Impedance Aggregometry
Poor platelet responsiveness to aspirin was usually defined as aggregation of at least 50% of platelets and represented the top quarter of samples. Only 2 studies examined the association between aspirin resistance detected by this method and clinical outcome, and they found that aspirin resistance was associated with cardiovascular events (see Table 4).49,50
Clinical Studies Based on Whole Blood Aggregomatry and the Ultegra RPFA-ASA System
The Ultegra RPFA-ASA
The Ultegra RPFA-ASA (Accumetrics, San Diego, CA) is a simple rapid bedside test that measures agglutination of fibrinogen-coated beads in response to propyl gallate or, more recently, arachidonic acid stimulation. If aspirin produces the expected antiplatelet effect, fibrinogen-coated beads will not agglutinate, and light transmission will not increase. The result is expressed as aspirin reaction units.4,51,52
Clinical Studies Based on the Ultegra RPFA-ASA
An Aspirin Reaction Unit of at least 550 usually indicated the absence of aspirin-induced platelet dysfunction and was defined as aspirin resistance. We also found only 2 studies, with controversial results (see Table 4).51,52
COMPARISON OF METHODS
Lordkipanidzé et al studied 201 patients with stable coronary artery disease receiving daily aspirin therapy (at least 80 mg). Platelet aggregation was measured by: (1) light transmission aggregometry (LTA) after stimulation with 1.6 mM of arachidonic acid (AA), (2) LTA after adenosine diphosphate (ADP) (5, 10, and 20 μM) stimulation, (3) whole blood aggregometry, (4) PFA-100, (5) VerifyNow Aspirin; urinary 11-dehydro-thromboxane B2 concentrations were also measured. They found that platelet function tests were not equally effective in measuring aspirin's antiplatelet effect and correlated poorly among themselves.5 Their result have been confirmed by other studies.6,53,54
On the other hand, a recent study based on healthy volunteers found high concordance (more than 90%) between the examined assays (light transmission aggregometry, PFA-100, VerifyNow, and urinary 11-dehydro-thromboxane B2).55
The broad use of statins, angiotensin receptor blockers, and selective serotonin reuptake inhibitors may be partially responsible for the lack of agreement among the laboratory tests because each of these drug classes inhibits platelets by different pathways.56 Our previous results showed the effect of different cardiovascular drugs on the laboratory efficacy of aspirin and clopidogrel.57,58
Despite the lack of definition of resistance and association of platelet function test, meta-analyses showed that patients who are “resistant” to aspirin are at greater risk of clinically important adverse cardiovascular events regardless of the assay used to measure aspirin resistance. Aspirin resistance did not only have an effect on clinical outcome, but this risk was not ameliorated by currently used adjunct antiplatelet therapies.7,8
HOW TO DEFINE ASPIRIN RESISTANCE?
The historical gold standard test of platelet function (light or optical aggregation) has well established limitations for measuring the antiplatelet effects of aspirin. Other tests for aspirin resistance might overcome some of these limitations, but they have not been standardized and do not correlate well with each other. The laboratory diagnosis of aspirin resistance is therefore highly test-specific. Unfortunately, a clinically meaningful, standardized definition of resistance based on data linking therapy-dependent laboratory tests to clinical outcomes has yet to be developed.
Furthermore, we mentioned above the platelet inhibition beyond conventional antiplatelet agents. Platelet function tests correlated poorly among themselves in the case of vascular diseased patients, but not in the case of healthy volunteers. These results underline the impotance of possible drug interactions, and suggest that the definition of resistance should be based on the difference between the pretreated and treated stages.
TREATMENT OF RESISTANCE
There are only a few studies examinig the possible treatment of aspirin resistance. Epidemiological studies suggest that Mediterranean diets are associated with a reduced risk of cardiovascular disease. It has been proposed that resveratrol is one of the most important dietary constituents involved in vasculoprotection. Resveratrol is one of a group of compounds called phytoalexins that are produced in plants during times of environmental stress such as microbial (fungal) infection or ultraviolet irradiation. Stef et al performed an in vitro study including 50 high-risk cardiac patients and showed that resveratrol effectively inhibited collagen- and epinephrine-induced aggregation of platelets from aspirin-resistant patients, which may contribute to its cardioprotective effects in this population.59
In the past decade, numerous studies have revealed a central role for NAD(P)H oxidases in cardiovascular pathophysiology.60 It is significant that recent studies demonstrated that functional NAD(P)H oxidase(s) were also expressed in platelets. Upon stimulation, platelets were shown to generate reactive oxygen species (ROS), which could be prevented by inhibitors of the NAD(P)H oxidase.60 Importantly, there is increasing evidence that NAD(P)H oxidase(s) play an important role in platelet aggregation.60 In another in vitro study, Stef et al examined 50 patients hospitalized after myocardial infarction or with stable or unstable angina pectoris or peripheral artery disease and/or scheduled for cardiac catheterization as potential candidates for percutaneous coronary intervention (PCI) and thus eligible in case of chronic treatment with ASA (more than 100 mg/d). They found that inhibition of NAD(P)H oxidase effectively suppressed collagen and epinephrine-induced aggregation of platelets from aspirin-resistant patients, which may represent a novel pharmacological target for cardioprotection in high-risk cardiac patients.60
Aprotinin, a drug effective in limiting blood loss in patients undergoing surgery, was first approved in the United States in 1993 for use in high-risk patients needing coronary artery surgery. In 1998, its use was broadened to include any patient undergoing coronary artery surgery using cardiopulmonary bypass.61
Aspirin is the only drug proven to reduce saphenous vein graft (SVG) failure, but aspirin resistance (ASA-R) frequently occurs after off-pump coronary artery bypass grafting (OPCAB). Poston et al supposed that thrombin production during OPCAB stimulates this acquired ASA-R. A nonrandomized prospective cohort of 255 patients (n = 465 SVG) who underwent OPCAB with varied use of aprotinin (21%) and different SVG preparation techniques (standard, 56% versus low-pressure, 44%) was analyzed. They found that ASA-R is a common post-OPCAB event whose frequency may be reduced by intraoperative use of aprotinin, possibly via TF and thrombin suppression. Improved perioperative PLT function after OPCAB may also inadvertently enhance the clinical relevance of these potential antithrombotic effects.61
A previous in vitro study showed the association between increased platelet response to ADP and aspirin resistance.62 Eikelboom et al raised the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin.63 In another study, the addition of clopidogrel to aspirin provided greater inhibition of platelets and could overcome aspirin resistance.64 Pamukcu et al found association between aspirin resistance and poor clinical outcome in ACS patients and also showed that the prevalence of major acute cardiac events in patients who were on clopidogrel treatment for 12 months. Poor clinical outcomes were significantly lower compared to those who were on a clopidogrel treatment for the first 6 months. In another study, aspirin resistance was also associated with worsening clinical outcome, but the poor outcome increased just after cessation of clopidogrel therapy.36,43
These results suggest that aspirin resistant patients may benefit from clopidogrel therapy. On the other hand, the meta-analysis by Krasopoulos et al showed that concomitant therapy with clopidogrel or tirofiban (an inhibitor of platelet glycoprotein IIb/IIIa) or both provided no benefit to those patients identified as aspirin-resistant.9 Further studies are needed to clarify their findings.
Patient (and doctor) education is also important. Biondi-Zoccai et al66 undertook a systematic review to appraise the hazards inherent to aspirin withdrawal or noncompliance in subjects at risk for or with CAD. From the 612 screened studies, 6 were selected (50,279 patients). They concluded that noncompliance or withdrawal of aspirin treatment has ominous prognostic implication in subjects with or at moderate-to-high risk for CAD. Aspirin discontinuation in such patients should be advocated only when bleeding risk clearly overwhelms that of atherothrombotic events.
FUTURE IMPLICATIONS
According to the most recent consensus statement on the use of antiplatelet agents and position paper on ASA resistance from the International Society on Thrombosis and Haemostasis, it is currently not recommended to test patients for ASA or clopidogrel resistance outside of clinical trials or to change therapy based on such testing.66,67 There are two main reasons for these recommendations.
First, a clinically meaningful, standardized definition of resistance based on data linking therapy-dependent laboratory tests to clinical outcomes has yet to be developed.68 Tests of platelet function in vitro are widely used in research and provide a mechanistic rationale for antiplatelet therapy. Correlating the results of such tests with clinical outcomes and using the results to guide therapy, however, remain challenging goals. We think, that drug interactions should be also considered. The ideal test of platelet function for use in clinical practice would be rapid, easy-to-use, inexpensive, and would be a reliable indicator of the clinical response to the specific antiplatelet therapy or combination of therapies. Prospective clinical trials are now needed. Second, the correct treatment of patients whose platelets are hyporesponsive to antiplatelet agents is unknown, given that no large, prospective study has assessed clinical effectiveness after altering therapy based on laboratory findings of hyporesponse.
REFERENCES
1. Antiplatelet Trialists Collaboration. Collaborative overview of randomized trials of antiplatelet therapy. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81-106.
2. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients. BMJ 2002;324:71-86.
3. Tantry US, Bliden KP, Gurbel PA. Resistance to antiplatelet drugs: current status and future research. Expert Opin Pharmacother. 2005;6:2027-2045.
4. Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet. 2006; 367:606-617.
5. Lordkipanidzé M, Pharand C, Schampaert E, et al. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J. 2007;28:1702-1708.
6. Gurbel PA, Bliden KP, DiChiara J, et al. Evaluation of dose-related effects of aspirin on platelet function. results from the Aspirin-Induced Platelet Effect (ASPECT) study. Circulation. 2007;115:3156-3164.
7. Michelson AD, Cattaneo M, Eikelboom JW, et al. Aspirin resistance: position paper of the Working Group on Aspirin Resistance, Platelet Physiology Subcommittee of the Scientific and Standardization Committee, International Society on Thromb Haemost. J Thromb Haemost. 2005;3:1309 -1311.
8. Snoep JD, Hovens MM, Eikenboom JC, et al. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch Intern Med. 2007;167:1593-1599.
9. Krasopoulos G, Brister SJ, Beattie WS, et al. Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ. 2008;336:195-198.
10. Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost. 2007;5(Suppl 1):230-237.
11. Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002;8:1227-1234.
12. Cattaneo M. Aspirin and clopidogrel. Efficacy, safety and the issue of drug resistance. Arterioscler Thromb Vasc Biol. 2004;24:1980-1987.
13. Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor? Blood. 2003;102:449-461.
14. Gawaz M. Role of platelets in coronary thrombosis and reperfusion of ischaemic myocardium. Cardiovasc Res. 2004;61:498-511.
15. Andrews RK, Gardiner EE, Shen Y, et al. Platelet interactions in thrombosis. IUBMB Life. 2004;56:13-18.
16. Awtry EH, Loscalzo J. Aspirin. Circulation. 2000;101;1206-1218.
17. Eikelboom JW, Hirsh J, White JI, et al. Aspirin resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke or cardiovascular death in patients at risk of high for cardiovascular event. Circulation. 2002;105:1650-1655.
18. Bruno A, McConnell JP, Cohen SN, et al. Serial urinary 11-dehydrothromboxane B2, aspirin dose, and vascular events in blacks after recent cerebral infarction. Stroke. 2004;35:727-730.
19. Valles J, Santos MT, Fuset MP, et al. Partial inhibition of platelet thromboxane A2 synthesis by aspirin is associated with myonecrosis in patients with ST-segment elevation myocardial infarction. Am J Cardiol. 2007;99:19-25.
20. 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.
21. Buchanan MR, Schwartz L, Bourassa M, et al. Results of the BRAT study-a pilot study investigating the possible significance of ASA nonresponsiveness on the benefits and risks of ASA on thrombosis in patients undergoing coronary artery bypass surgery. Can J Cardiol. 2000;16:1385-1390.
22. Gum PA, Kottke-Marchant K, Welsh PA, et al. 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.
23. Cotter G, Shemesh E, Zehavi M, et al. Lack of aspirin effect: aspirin resistance or resistance to taking aspirin? Am Heart J. 2004;147:293-300.
24. Berrouschot J, Schwetlick B, von Twickel G, et al. Aspirin resistance in secondary stroke prevention. Acta Neurol Scand. 2006;113:31-35.
25. Faraday N, Braunstein JB, Heldman AW, et al. Prospective evaluation of the relationship between platelet-leukocyte conjugate formation and recurrent myocardial ischemia in patients with acute coronary syndromes. Platelets. 2004;15:9-14.
26. Zhang Y, Liang J, Zhou YJ, et al. Study on the relationship between aspirin resistance and incidence of myonecrosis after non-emergent percutaneous coronary intervention. Zhonghua Xin Xue Guan Bing Za Zhi. 2005;33:695-659.
27. Tantry US, Bliden KP, Gurbel PA. Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation. J Am Coll Cardiol. 2005;46:1705-1709.
28. Cornelissen J, Kirtland S, Lim E, et al. Biological efficacy of low against medium dose aspirin regimen after coronary surgery: analysis of platelet function. Thromb Haemost. 2006;95:476-482.
29. Ohmori T, Yatomi Y, Nonaka T, et al. Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity: involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients. J Thromb Haemost. 2006;4:1271-1278.
30. Stejskal D, Václavík J, Lacnák B, et al. Aspirin resistance measured by cationic propyl gallate platelet aggregometry and recurrent cardiovascular events during 4 years of follow-up. Eur J Intern Med. 2006;17:349-354.
31. Lev EI, Patel RT, Maresh KJ, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol. 2006;47:27-33.
32. Geisler T, Kapp M, Göhring-Frischholz K, et al. Residual platelet activity is increased in Clopidogrel- and ASA-treated patients with coronary stenting for acute coronary syndromes compared with stable coronary artery disease. Heart. 2007 Jun 13 [Epub ahead of print]
33. Kundu SK, Heilmann E, Sio R, Garcia C, et al. Characterisation of an in vitro platelet function analyser, PFA-100TM. Clin Appl Thromb Hemost. 1996;2:241-249.
34. Marcucci R, Paniccia R, Antonucci E, et al. Usefulness of aspirin resistance after percutaneous coronary intervention for acute myocardial infarction in predicting one-year major adverse coronary events. Am J Cardiol. 2006;98:1156-1159.
35. Poulsen TS, Jørgensen B, Korsholm L, et al. Prevalence of aspirin resistance in patients with an evolving acute myocardial infarction. Thromb Res. 2007;119:555-562.
36. Pamukcu B, Oflaz H, Onur I, et al. Clinical relevance of aspirin resistance in patients with stable coronary artery disease: a prospective follow-up study (PROSPECTAR). Blood Coag Fibr. 2007;18:187-192.
37. Poulsen TS, Mickley H, Korsholm L, et al. Variation and importance of aspirin resistance in patients with known cardiovascular disease. Thromb Res. 2007;120:477-484.
38. Andersen K, Hurlen M, Arnesen H, et al. Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease. Thromb Res. 2002;108:37-42.
39. Yilmaz MB, Balbay Y, Caldir V, et al. Late saphenous vein graft occlusion in patients with coronary bypass: possible role of aspirin resistance. Thromb Res. 2005;115:25-29.
40. Grundmann K, Jaschonek K, Kleine B, et al. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks. J Neurol. 2003;250:63-66.
41. Gulmez O, Yildirir A, Kaynar G, et al. Effects of persistent platelet reactivity despite aspirin therapy on cardiac troponin I and creatine kinase-MB levels after elective percutaneous coronary interventions. J Thromb Thrombol. 2007 Jun 16 [Epub ahead of print].
42. Małek ŁA, Spiewak M, Filipiak KJ, et al. Persistent platelet activation is related to very early cardiovascular events in patients with acute coronary syndromes. Kardiol Pol 2007;65:40-45.
43. Pamukcu B, Oflaz H, Oncul A, et al. The role of aspirin resistance on outcome in patients with acute coronary syndrome and the effect of clopidogrel therapy in the prevention of major cardiovascular events. J Thromb Thrombol. 2006;22:103-110.
44. Pamukcu B, Oflaz H, Nisanci Y. The role of platelet glycoprotein IIIa polymorphism in the high prevalence of in vitro aspirin resistance in patients with intracoronary stent restenosis. Am Heart J. 2005;149:675-680.
45. Hobikoglu GF, Norgaz T, Aksu H, et al. The effect of acetylsalicylic acid resistance on prognosis of patients who have developed acute coronary syndrome during acetylsalicylic acid therapy. Can J Cardiol. 2007;23:201-206.
46. Borna C, Lazarowski E, van Heusden C, et al. Resistance to aspirin is increased by ST-elevation myocardial infarction and correlates with adenosine diphosphate levels. Thromb J. 2005;3:10.
47. Hobikoglu GF, Norgaz T, Aksu H, et al. High frequency of aspirin resistance in patients with acute coronary syndrome. Tohoku J Exp Med. 2005;207:59-64.
48. Atiemo AD, Ng'alla LS, Vaidya D, et al. Abnormal PFA-100 closure time is associated with increased platelet aggregation in patients presenting with chest pain. J Thromb Thrombol. 2008;25:173-178.
49. Poston RS, Gu J, Brown JM, et al. Endothelial injury and acquired aspirin resistance as promoters of regional thrombin formation and early vein graft failure after coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2006;131:122-130.
50. Mueller MR, Salat A, Stangl P, et al. Variable platelet response to low-dose ASA and the risk of limb deterioration in patients submitted to peripheral arterial angioplasty. Thromb Haemost. 1997;78:1003-1007.
51. Buch AN, Singh S, Roy P, et al. Measuring aspirin resistance, clopidogrel responsiveness, and postprocedural markers of myonecrosis in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2007;99:1518-1522.
52. Chen WH, Lee PY, Ng W, et al. 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.
53. Harrison P, Segal H, Silver L, et al. Lack of reproducibility of assessment of aspirin responsiveness by optical aggregometry and two platelet function tests. Platelets. 2008;19:119-124.
54. Chakroun T, Addad F, Abderazek F, et al. Screening for aspirin resistance in stable coronary artery patients by three different tests. Thromb Res. 2007;121:413-418.
55. Karon BS, Wockenfus A, Scott R, et al. Aspirin responsiveness in healthy volunteers measured with multiple assay platforms. Clin Chem. 2008 Apr 17 [Epub ahead of print].
56. Malinin AI, Ong S, Makarov LM, et al. Platelet inhibition beyond conventional antiplatelet agents: expanding role of angiotensin receptor blockers, statins and selective serotonin reuptake inhibitors. Int J Clin Pract. 2006;60:993-1002.
57. Feher G, Koltai K, Alkonyi B, et al. Clopidogrel resistance: role of body mass and concomitant medications. Int J Cardiol. 2007;120:188-192.
58. Feher G, Koltai K, Papp E, et al. Aspirin resistance: possible roles of cardiovascular risk factors, previous disease history, concomitant medications and haemorrheological variables. Drugs Aging. 2006;23:559-567.
59. Stef G, Csiszar A, Lerea K, et al. Resveratrol inhibits aggregation of platelets from high-risk cardiac patients with aspirin resistance. J Cardiovasc Pharmacol. 2006;48:1-5.
60. Stef G, Csiszar A, Ziangmin Z, et al. Inhibition of NAD(P)H oxidase attenuates aggregation of platelets from high-risk cardiac patients with aspirin resistance. Pharmacol Rep. 2007;59:428-436.
61. Poston RS, Gu J, White C, et al. Perioperative management of aspirin resistance after off-pump coronary artery bypass grafting: possible role for aprotinin. Transfusion. 2008;48(Suppl 1):39S-46S.
62. Macchi L, Christiaens L, Brabant S, et al. Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate. Thromb Res. 2002;107:45-49.
63. Eikelboom JW, Hankey GJ, Thom J, et al. Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial. J Thromb Haemost. 2005;3:2649-2455.
64. Dropinski J, Jakiela B, Sanak M, et al. The additive antiplatelet action of clopidogrel in patients with coronary artery disease treated with aspirin. Thromb Haemost. 2007l;98:201-209.
65. Biondi-Zoccai GG, Lotrionte M, Agostoni P, et al. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J. 2006;27:2667-2674.
66. Task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European Society of Cardiology: Expert consensus document on the use of antiplatelet agents. Eur Heart J. 2004;25:166-181.
67. Michelson AD, Cattaneo M, Eikelboom JW, et al. Aspirin resistance: position paper of the Working Group on Aspirin Resistance. J Thromb Haemost 2005;3:1309-1311.
68. Braunwald E, Angiolillo D, Bates E, et al. Assessing the current role of platelet function testing. Clin Cardiol 2008;31(Suppl 1):I10-I16.
Keywords:
aspirin; antiplatelet agent; aspirin resistance; cardiovascular outcome; platelet aggregation
© 2008 Lippincott Williams & Wilkins, Inc.