Journal of Vascular Surgery
Volume 50, Issue 6 , Pages 1500-1510, December 2009

Current evidence and clinical implications of aspirin resistance

  • George Kasotakis, MD

      Affiliations

    • Department Surgery, Creighton University Medical Center, Omaha, Neb
    • ,
  • Iraklis I. Pipinos, MD

      Affiliations

    • Division of Vascular Surgery, University of Nebraska Medical Center, Omaha, Neb
    • ,
  • Thomas G. Lynch, MD

      Affiliations

    • Division of Vascular Surgery, University of Nebraska Medical Center, Omaha, Neb
    • Corresponding Author InformationReprint requests: Thomas G. Lynch, MD, University of Nebraska Medical Center, Department of Surgery, 983280 Nebraska Medical Center, Omaha, NE 68198-3280

Received 20 March 2009; accepted 14 June 2009. published online 13 August 2009.

Richard P. Cambria, MD, Section Editor

Article Outline

Atherothrombosis, characterized by atherosclerotic plaque rupture and subsequent occlusive or subocclusive thrombus formation is the primary cause of acute ischemic syndromes involving all vascular beds and accounts for more than one-third of all deaths in the developed world. Platelet activation and aggregation constitute the most critical component in the pathophysiology of atherothrombotic disease. Aspirin is currently the most commonly used antiplatelet agent and one of the most frequently prescribed drugs, with as many as 30 million Americans on chronic aspirin regimens. Multiple well-designed prospective randomized clinical trials have demonstrated aspirin's efficacy in both primary and secondary prevention of a wide variety of entities that the atherothrombotic disease spectrum encompasses, such as cerebrovascular, coronary artery, and peripheral vascular disease. Despite its proven benefit, however, a growing body of evidence suggests that up to 70% of aspirin-takers may still be at risk for atherothrombotic complications due to resistance. Patients with laboratory-confirmed aspirin resistance seem to have an almost fourfold increase in their risk for acute thrombotic episodes, which underlines the magnitude of the problem for the vascular specialist. In this article, we review the physiology of platelet activation and the role of aspirin as an antiplatelet agent; the various laboratory assays used in assessing aspirin effectiveness; and current data on aspirin resistance and its clinical implications in patients with cardiovascular disease. We also review the studies that explore this phenomenon in patients with peripheral arterial disease and discuss the optimal management options in aspirin-resistant individuals. Suggestions are advanced for the direction of future trials evaluating aspirin resistance in patients with vascular disease.

 

Atherothrombosis, characterized by atherosclerotic lesion disruption with associated thrombotic complications, is the primary cause of acute ischemic syndromes involving all vascular beds and accounts for up to 35% of all deaths in the developed world.1 In a meta-analysis of 287 randomized trials involving more than 200,000 patients, the Antithrombotic Trialists' Collaboration has demonstrated a 22% reduction in morbidity and mortality from serious ischemic cardiovascular episodes with aspirin therapy compared to placebo.2 As a result, aspirin (acetylsalicylic acid [ASA]) has become the most cost-effective and widely used agent in the primary and secondary prevention of atherosclerotic disease, with an estimated 30 million Americans on a chronic aspirin regimen. However, despite its wide acceptance and utilization, aspirin's antiplatelet effect is not uniform and persistent platelet reactivity has been demonstrated in up to 70% of patients on aspirin therapy3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 (Table I), suggesting that up to 21 million Americans on aspirin regimens may not enjoy its beneficial cardiovascular effects. In this article, we review the currently available data on aspirin resistance; its prevalence and etiology; the laboratory assays used to assess aspirin effect; and the implications of aspirin resistance in the practice of vascular surgery.

Table I. Prevalence of aspirin resistance as diagnosed by laboratory assays in various clinical settings
Clinical settingInvestigatorn =Platelet assayASA dose (mg)Prevalence
CVDGrundmann et al353PFA-10010022.6%
CVDAlberts et al439PFA-1008156.0%
CVDAlberts et al487PFA-10032528.0%
CVDMcCabe et al547PFA-10075-30046.8%
CVDBerrouschot et al6240LTA30012.5%
CVDHelgason et al7306LTA325-130025.5%
CVDGrotemeyer et al8306LTA32525.0%
CVDGrotemeyer9180PR150033.0%
CABGZimmermann et al1020LTA10015.0%
CABGYilmaz et al1114PFA-10080-3257.1%
CABGBuchanan1240BT32542.0%
CABGBuchanan13289BT32554.0%
CABGPoston et al14225IA,TXB2levels,TEG,CD62p32521.8%
PCIChen et al15151RPFA81-32519.2%
PCIZhang et al16256LTA10026.2%
PCILev et al17150LTA81-32512.7%
PCIGurbel et al18191TEG81-32523.6%
Stable CADMacchi et al19160PFA-1009829.0%
Stable CADChristiaens et al2050PFA-10075-30020.0%
Stable CADPamukcu et al2162PFA-10030012.9%
Stable CADMacchi et al2272PFA-10016029.2%
Stable CADGum et al23325PFA-1003259.5%
Stable CADGum et al23325LTA3255.5%
Stable CADFriend et al24325LTA5625.0%
Stable CADTantry et al25223LTA3250.4%
Stable CADLee et al26468RPFA81-32527.0%
MIBorna et al2764PFA-10075-32531.3%
MIAndersen et al2858PFA-1007540.0%
MIAndersen et al2871PFA-10016035.0%
MIHobikoglu et al29204PFA-100100-30033.8%
MIStejskal et al30103LTA10070.1%
MIFaraday et al3130LTA3256.7%
MISchwartz et al32190LTA81-3250.5%
MICotter et al3361TXB2levels10014.7%
CHFSane et al3488PFA-10032555.0%
CEAPayne et al3550LTA15056.0%
Post-CEAAssadian et al3686PFA-10010016.0%
PVDZiegler et al3752PFA-1001009.6%
PVDMueller et al38100LTA32560.0%
Risk factorsMalinin et al39141LTA3250.7%
Risk factorsMalinin et al39141RPFA3257.0%
Risk factorsWang et al40422RPFA81-32523.4%
Healthy adultsMarshall et al4112PFA-100,BT22508.3%
Various patientsHillarp et al42122IA75-1600.8%

CVD, Cerebrovascular disease; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; CAD, coronary artery disease; MI, myocardial infarction; CHF, congestive heart failure; CEA, carotid endarterectomy; PVD, peripheral vascular disease; PFA-100, platelet function analysis; LTA, light transmission aggregometry; PR, platelet reactivity; BT, bleeding time; IA, impedance aggregometry; TEG, thromboelastography; RPFA, rapid platelet function assay; TXB, thromboxane B; CD62p, CD62p flow cytometry.

The aspirin dose, the platelet assay utilized, and the number of individuals participating in each study are shown. As few as 0.4% or as many as 70% of chronic aspirin takers may be resistant to the medication.

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Aspirin: the history 

ASA - more commonly known as aspirin - is one of the oldest medications still in wide availability. Early accounts indicate that Hippocrates used willow leaves, rich in ASA, to relieve the aches associated with multiple illnesses in ancient Greece.43 Reverend Edmund Stone was able to isolate salicilin, the glycoside of salicylic acid and the active ingredient of aspirin, from the bark of a willow tree in England in 1763.44 This ‘newly’ discovered compound was named for the Salix Alba, literally white willow. In the 1800s, various scientists were able to streamline the extraction of salicylic acid from willow bark, but it was not until 1897 that Felix Hoffmann, a German chemist working for Friedrich Bayer, was able to develop a well-tolerated compound and ASA was born.45 Bayer marketed aspirin in 1899 and dominated the flourishing market of pain relievers.43 Since then, aspirin has grown to become one of the most commonly identified trade names around the globe and one of the most commercially successful drugs. In the modern medical literature, the antithrombotic effects of aspirin were first reported in the Mississippi Valley Medical Journal in 1953.46 Since then, numerous studies have confirmed aspirin's antiplatelet effect, establishing its therapeutic efficacy and validating its widespread use.

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Mechanism of action 

Platelets in hemostasis 

Upon injury of the blood vessel intima, as it occurs after trauma or rupture of an atherosclerotic plaque, subendothelial collagen and von Willebrand factor (vWF) are exposed to circulating blood components. Platelets adhere to both collagen and vWF on the injured endothelium through their glycoprotein Ia/IIa and Ib/V/IX receptors, respectively,47 eliciting the release of calcium. Calcium induces a conformational change in the platelet glycoprotein IIb/IIIa (gp IIb/IIIa) receptors, so they are able to bind circulating fibrinogen molecules. Calcium also stimulates the release of α-granules and dense granules. P-Selectin, one of the proteins released from α-granules, mediates the adhesion of monocytes and neutrophils to activated platelets.48 This function is integral to the recruitment of leukocytes into newly-formed thrombi, the perpetuation of thrombogenesis, and the overall hemostatic process.48 Dense granules release adenosine diphosphate (ADP), which further perpetuates platelet activation by binding to ADP-specific receptors (P2Y1) and promotes the action of phospholipase A2 on membrane phospholipid compounds to produce arachidonic acid (ARA).49 Arachidonic acid is subsequently converted into thromboxane A2 (TXA2) and prostaglandins (mainly G2 and H2) within platelets, a conversion mediated by thromboxane synthase and the cyclooxygenase (COX) isoenzymes 1 and 2, respectively.50 TXA2 is the most important platelet activator and functions by inducing expression of fibrinogen receptors (gp IIb/IIIa) on the platelet membrane and by binding to TXA2 receptors on the surface of other platelets triggering their activation.49 It also plays a secondary, but equally important role in hemostasis, as a potent vasoconstrictor. Platelet activation also occurs with the attachment of other freely circulating nascent compounds, such as ADP, fibrinogen, thrombin, adrenalin, and prostaglandin I2, to corresponding ligand-specific receptors49 (Fig).

  • View full-size image.
  • Fig. 

    Mechanisms for platelet activation: substances in the top of the figure correspond to the most common platelet activators that exert their mechanism attaching to specialized platelet surface receptors. Pathway-specific platelet antagonists appear in red.

Aspirin effect on platelet activation 

Aspirin irreversibly inhibits COX-1 in platelets by acetylating its serine-529 residue, thereby blocking TXA2 and other eicosanoid production from ARA. TXA2 is the most significant trigger for platelet activation and because platelets lack a nucleus, and therefore are deprived of proteinosynthetic ability, this inhibition cannot be overcome by new COX-1 synthesis and thus lasts for the platelet's lifespan (7-10 days). Aspirin-induced COX-1 inhibition is rapid, irreversible, and saturable at low doses (dose-independent).49 After a single 325 mg dose of ASA, platelet COX-1 activity is completely inhibited and recovers by about 10% per day, due to nascent platelet release in the circulation.49

Aspirin metabolism 

Appreciable aspirin concentrations are found in plasma in less than 30 minutes after ingestion. After a single dose, a peak value is reached in about 1 hour and then declines gradually, with a half-life of about 2-3 hours at antiplatelet doses.51 This is a result of hydrolysis in the liver (hepatic endoplasmic reticulum and mitochondria), plasma (by freely circulating hydrolases), and erythrocytes. As mentioned earlier, COX-1-dependent TXA2 inhibition lasts throughout a platelet's lifespan, thereby aspirin effects are maintained with daily dosing intervals. At the concentrations encountered clinically, roughly 80% to 90% of the salicylate in plasma is bound to albumin; the percentage that is protein-bound declines as concentrations increase. Hypoproteinemia and a variety of other compounds that compete with aspirin for plasma protein binding sites (such as thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, bilirubin, uric acid, penicillins, and other nonsteroidal anti-inflammatory drugs) as a consequence, are associated with proportionately higher levels of free salicylates in the bloodstream.51, 52

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Aspirin resistance: laboratory evaluation 

Aspirin resistance can either be identified on clinical grounds or detected with laboratory tests that assess platelet activation. Clinical resistance refers to the drug's inability to prevent clinical atherothrombotic events in patients treated with ASA. However, the latter phenomenon should more accurately be referred to as aspirin treatment failure, because not all reports of atherothrombotic events take into account potential patient noncompliance. Laboratory aspirin resistance, on the other hand, is defined as ASA failure to inhibit platelet aggregation in a predictable, measurable fashion.50, 53

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Platelet assays 

Numerous assays have been developed to measure platelet reactivity and, hence, indirectly quantify aspirin's antiplatelet effect. However, when attempting to interpret studies investigating laboratory-identified ASA resistance, it should be taken into account that most of these assays measure platelet aggregation that may not necessarily be specific for TXA2-induced platelet reactivity. Therefore, laboratory studies may indicate an individual is ASA-resistant if platelets are aggregating from a trigger other than TXA2, even though aspirin might be effectively inhibiting COX-1, its sole target. The studies that utilize ASA metabolites are a notable exception.

Due to its simplicity, the most commonly utilized assay is the Platelet Function Analyzer-100 (PFA-100; Dade-Behring, Deerfield, Ill). However, Light Transmission Aggregometry (LTA) (Accumetrics Inc, San Diego, Calif) remains the “gold standard” for monitoring platelet function, despite being more demanding technically.

Bleeding time 

Bleeding time (BT) provides an indirect measure of the time needed for a platelet plug to form when a puncture of standardized dimensions is made on the skin and is the only platelet assay that can be performed in vivo. BT is relatively independent of coagulation factor disorders (it is normal in patients with hemophilia) and, therefore, a fairly good gauge of platelet function. However, it assumes that capillary function is normal. Falsely-elevated results can be seen in thrombocytopenic individuals, patients with disseminated intravascular coagulation, vWF, and less frequently in coumadinized patients.

Thromboxane and aspirin metabolites 

Stable metabolites of TXA2, such as serum TXB2 or urinary 11-dehydro-TXB2, have been used by many to evaluate aspirin resistance.14, 33 These tests do not directly measure platelet reactivity and are not platelet-specific: TXA2 is also produced by monocytes, macrophages, endothelial cells, and perhaps platelets through the action of COX-2 and, therefore, may lead to TXB2 production that occurs regardless of platelet-derived TXA2 inhibition. For this reason, use of TXA2 metabolites to assess aspirin resistance has been mostly abandoned, and is only useful in monitoring compliance. Similarly, aspirin metabolites have not been used to assess resistance, due to significant interindividual variability in salicylate metabolism.

Light transmission and impedance aggregometry 

LTA quantifies platelet activation in vitro using an aggregometer that measures the optical density of platelet-rich plasma (obtained with centrifugation) after platelet aggregation is induced with the addition of an agonist, such as ARA, thrombin, collagen, epinephrine, or ADP. Although an indirect index, LTA is considered the “gold standard” for monitoring platelet function.50 Impedance aggregometry (IA) is based on the same principle, but uses whole blood and measures electric impedance instead of light transmission. This technique is simpler and more practical than LTA because it does not require sample centrifugation.50

PFA-100 

The assay simulates the in vivo function of platelets in primary hemostasis and can be regarded as an in vitro bleeding time recorder.54 In this test (Dade-Behring), a whole blood sample aspirated from a capillary is anticoagulated with citrate and then run through a cartridge coated with a platelet agonist (collagen/ADP or epinephrine). The cartridge has a hole of standardized dimensions in its center. Irreversible platelet aggregation results in formation of a stable platelet plug which closes the central hole. The time required for blood flow cessation is expressed as closure time (higher values indicate aspirin nonresponsiveness) and provides a measure of platelet hemostatic capacity.50

Rapid platelet function assay (RPFA) 

In this point-of-care test, sampled capillary blood is run through a transparent fibrinogen-coated cartridge that contains platelet agonists, such as ARA, collagen, or epinephrine (Accumetrics Inc). As thrombus is formed on its surface, light transmission through the cartridge changes, providing an indirect measure of platelet activation.

Platelet reactivity (PR) 

The PR test measures platelet activation triggered by a standardized vascular injury. Blood from a forearm vein is sampled in a standardized fashion and then mixed with either EDTA-buffer or EDTA-formaldehyde-buffer, respectively. While in the EDTA-buffer, the activated platelets are dissolved while they remain fixed in the EDTA-formaldehyde medium. Centrifugation causes only unattached, nonactivated platelets to remain in the supernatant and a platelet counter determines the numbers in each supernatant. The measurement is inversely proportional to the number of unattached platelets.

Flow cytometric analysis 

Flow cytometry has been employed in recent studies to assess activation-dependent changes in the surface expression of platelet receptors. Serebruany et al55 studied platelet activation after stroke or transient ischemic attack in patients on aspirin and those who were aspirin-free. Using monoclonal antibodies, they assessed expression of GPIIb/IIIa (CD41); GPIb (CD42b); P-Selectin (CD62p); GPIIb/IIIa activity (PAC-1); platelet/endothelial cell adhesion molecule, PECAM-1 (CD31); vitronectin receptor (CD51/CD61); lysosome-associated membrane protein, LAMP-3 (CD63), LAMP-1 (CD107a); platelet endothelial tetraspan antigen, PETA-3 (CD151); CD40-ligand (CD154); thrombospondin (CD36), and platelet-leukocyte aggregates (CD151, CD14). Thrombospondin, GPIIb/IIIa, P-Selectin, CD40-ligand, and platelet-monocyte aggregates were significantly lower in the aspirin-treated group. Hezard et al56 found little correlation between the PFA-100, platelet aggregometry, and GPIIb/IIIa flow cytometry in patients receiving various platelet regimens.

P-Selectin is typically induced after ARA stimulation and thereby provides an indirect assessment of ARA-induced platelet aggregation.36 Flow cytometry for P-Selectin expression seems promising as it is quite specific for ASA use and yields results comparable to those obtained with aggregometry,50, 57 although at least one study demonstrated that all patients receiving aspirin demonstrated arachidonic acid induced expression of CD62p (P-Selectin), using flow cytometry, whereas PFA-100 closure times indicated 16% of patients taking aspirin showed no effect of aspirin.36 The general characteristics of the assays currently in use are summarized in Table II.

Table II. Laboratory assays used in the diagnosis of aspirin resistance
AdvantagesLimitations
In vivo assays
Bleeding time
* The only in vivo test

* Easy to perform, cheap, available at point-of-care

* Independent of coagulation disorders


* Not ASA specific

* Dependent on von Willebrand, platelet count, anticoagulant use

* Poor reproducibility

* Poor correlation with other platelet function assays

In vitro assays
Thromboxane production assays
Serum TXB2
* Directly dependent on aspirin's therapeutic target, COX-1

* Indirect measure of compliance


* Not platelet-specific

* Operator-dependent

Urinary 11-dehydro-TXB2* As above
* Uncertain sensitivity, reproducibility

* Not widely evaluated

Thromboxane-dependent platelet function assays
Light transmission aggregometry
* Traditional ‘gold standard’

* Correlates with clinical events

* Requires significant sample preparation


* Not ASA-specific

* Limited availability

* Operator dependent

* Expensive and labor intensive

* Not standardized

* Depends on age, gender, race, diet, hematocrit

Impedance aggregometry
* Minimal sample preparation required

* Independent of platelet count

* As above
PFA-100
* Simple, rapid, inexpensive

* Sensitive

* Available at point of care

* Semi-automated

* Correlates with LTA


* Not ASA specific

* Depends on von Willebrand factor and hematocrit

Ultegra (RPFA)* As above
* Not ASA specific

* Depends on von Willebrand factor and hematocrit

* Less sensitive than PFA-100

Platelet reactivity
* Simple, standardized


* Not ASA specific

* Limited testing

* Uncertain sensitivity

Activation-dependent changes in platelet surface
P-Selectin (CD62p) flow-cytometric analysis
* Correlates well with LTA

* Low sample volume

* Whole blood assay

* Promising method


* Not widely used nor thoroughly validated

* Uncertain sensitivity

* Expensive sample preparation

* Experience in flow cytometry required

Platelet surface activated GP IIb/IIIa
* Low sample volume

* Whole blood assay


* As above

* Poor correlation with PFA-100

Leukocyte-platelet aggregates flow cytometry* As above
* As per P-Selectin analysis

ASA, Acetylsalicylic acid; TXB, thromboxane B; COX, cyclooxygenase; PFA-100, platelet function analysis; RPFA, rapid platelet function assay; LTA, light transmission aggregometry; CD62p, CD62p flow cytometry.

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Mechanisms for aspirin resistance 

The concept of therapeutic resistance emerged with the clinical observation that chronic aspirin-takers are not invariably protected from acute cardiovascular events, even though such an expectation would be overly optimistic, given that only a 22% of aspirin-takers had demonstrated a therapeutic advantage, as evidenced in the Antithrombotic Trialist Collaboration study.2 Significant variability in platelet function has also been demonstrated in aspirin-treated patients in multiple clinical settings including healthy individuals,41 with risk factors,39, 40 and patients with coronary,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 peripheral vascular37, 38 or cerebrovascular disease.3, 4, 5, 6 Unfortunately, due to lack of a consensus definition and universally accepted diagnostic criteria, the term aspirin resistance has been used in miscellaneous clinical studies with diverse patient populations, different aspirin regimens, and different assays for assessment of the effect. This has resulted in reports of aspirin resistance ranging from 0.4%25 to as high as 70%,30 further confusing our understanding of this phenomenon.

Noncompliance 

With up to 40% of cardiovascular patients possibly being nonadherent with their regimens, one obvious explanation for aspirin treatment failure is noncompliance.32, 33, 58 Confirmed nonadherent patients are significantly more likely to experience recurrent acute cardiovascular episodes when compared to their biologically-resistant counterparts.33 Unfortunately, there is no widely accepted gold standard for the assessment of compliance. Continuous intake observation is not feasible on an outpatient basis, verbal confirmation of aspirin intake by patients is not always reliable, pill counts can be misleading when medications are being discarded instead of ingested; video surveillance in an in-patient setting can be burdened with behavioral modification on the patient's behalf when they know they are being observed (Pygmalion effect); and finally salicylate level measurement, although objective, can be deceptive due to aspirin's short half-life (about 30 minutes) and would fail to identify individuals who only take their medications in anticipation of a doctor's appointment (“white coat compliance”).59 Considering the relatively high prevalence of noncompliance, many authors have suggested that it is the predominant cause of resistance.32, 33, 36, 58, 60, 61, 62, 63

TXA2 independent platelet activation pathways 

It is well recognized that platelets can be activated independently of TXA2 synthesis64, 65, 66 and cannot, therefore, be inhibited by ASA. This can occur via platelet membrane receptors for ADP (P2Y1), thrombin and epinephrine, and glycoprotein receptors for collagen (Ia/IIa), vWF (Ib/V/IX), and fibrinogen (GP IIb/IIIa), as stated earlier.49 In fact, it has been shown that the in vitro response of platelets to ADP22 and collagen67 is much more pronounced in aspirin-resistant individuals; and in vivo platelet activation at the site of vascular injury in coronary artery disease seems to be induced mainly through ADP-mediated pathways.68 Hereditary polymorphisms in the platelet membrane collagen,69 ADP (P2Y1),19 fibrinogen and vWF (GP IIIa)70, 71, 72, 73 receptors have also been shown to alter platelet reactivity, significantly blunting the aspirin effect. In the case of the GP IIIa receptor, certain alleles have been associated with a significantly higher incidence of ischemic heart disease and acute coronary events70, 71, 74, 75 and could function as important predictors for sudden cardiac death.76

Alternative routes of TXA2 production 

On a molecular level, ASA does not inhibit TXA2 synthesis, that can also be generated by COX-2 in monocytes, macrophages,64, 77 megakaryocytes, and a subpopulation of immature platelets that carry this COX isoenzyme,78, 79, 80 This is especially true when the numbers of these inflammatory cells are increased (after atherothrombotic events or embolic phenomena that cause cellular death, such as after a myocardial infarction or an acute ischemic stroke),10 and in high platelet turnover states (such as recent surgery, infection, and active atherosclerosis).80 COX-1 gene mutations that decrease its affinity to aspirin have also been identified.42, 81 Finally, individuals with regenerating or inducible COX-1 in their megakaryocytes can demonstrate proportionally greater platelet activation with prolonged aspirin intake (tachyphylaxis).82

Inadequate dosing 

Various randomized controlled trials have demonstrated that daily, low-dose aspirin therapy can suppress COX-1,83, 84, 85, 86 corroborating the finding that 325 mg of aspirin may not offer additional COX inhibition compared to 81 mg, as this process is rapid, irreversible, and saturable at low doses (dose-independent), as stated earlier.49 Even though an across-the-board consensus on the ideal aspirin dosage for primary and secondary prevention of atherothrombotic events seems to be lacking,87, 88 higher doses seem to be more effective in clinical trials that use laboratory endpoints to measure aspirin resistance.7, 19, 26, 28, 89, 90, 91, 92, 93, 94, 95, 96 However, these findings were not confirmed in studies with clinical outcome endpoints97 and meta-analyses of studies assessing the clinical significance of laboratory-identified ASA resistance have failed to demonstrate a similar dose-dependent effect.98

Variability in aspirin pharmacodynamics and pharmacokinetics (absorption, bioavailability, metabolism, and excretion) 

Absorption of orally ingested salicylates occurs rapidly by passive diffusion across the gastric and proximal small bowel mucosa and is influenced by gastric pH. Rise in the pH enhances absorption mainly because it accelerates dissolution of the tablets. Acid-lowering medications, therefore, accelerate absorption whereas presence of food delays it.51 Although still in the bowel, a small proportion of ingested salicylates can be inactivated by esterases present in the intestinal brush border. Once in the bloodstream, ASA is broken down by the liver, red blood cells, and freely circulating plasma hydrolases.99, 100, 101 Interindividual variability in expression of the enzymes participating in aspirin metabolism may be partially responsible for failure of aspirin to inactivate platelets. Furthermore, once in the bloodstream, ASA competes with a variety of other medications (such as thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, penicillins, and other NSAIDs) and compounds (bilirubin, uric acid) for protein binding sites. Presence of these medications lead to higher free plasma salicylate levels, which may transiently increase its antiplatelet effect, but will eventually render it more susceptible to the innate hydrolytic mechanisms. Finally, changes in urinary pH can affect the rate of salicylate elimination, with more alkaline urine eliminating aspirin derivatives faster.51

Smoking 

Even though quality data suggesting a direct link between smoking and aspirin resistance are currently lacking, it seems that smokers are more likely to be found resistant by PFA-100 analysis compared with their nonsmoking counterparts (33.3% vs 12.5%; P = .05).22 This finding seems to be a result of the known procoagulant properties that chronic smoking has, even despite aspirin use.102

Duration of regimen 

Although adequate platelet inhibition may be achieved in the first month of aspirin treatment,9, 85, 100 loss of the therapeutic advantage has been confirmed in individuals on long-term treatment, particularly on regimens greater than 500 days in duration.7, 23, 82 This effect, that is demonstrated with laboratory assays, coincides with an increase of adverse cardiovascular outcomes in aspirin users.103, 104 Even though the mechanism of this phenomenon is not well understood, late tachyphylaxis, progression of atherosclerosis, inducible COX-1, and perhaps most importantly, decreasing adherence have all been postulated as plausible etiology.82

Lack of consensus on aspirin resistance definition 

The lack of a universally accepted, standardized laboratory definition of aspirin resistance has led to a wide variation in the reported prevalence. This is possibly a reflection of the tests utilized (Table I), different agonists or even different reference ranges used within the same method, and finally the dissimilar patient population assessed in each study. The prevalence of aspirin resistance ranges between 1% to 56% when the PFA-100 test is used, and between 7% to 27% when the RPFA assay is utilized. With LTA, however, the reported prevalence seems to be wider, from 0.4% to 70%. Depending on what test is used, it is possible that as few as 120,000, or as many as 21 million, Americans who are on chronic aspirin therapy could be ASA-resistant and therefore susceptible to acute atherothrombotic episodes.

Based on the published data to date, and irrespective of the laboratory test used, it seems that the antiplatelet effects of aspirin seem to be variable among individuals105 and probably have a continuous, broad distribution, which not only varies among individuals, but also in the same person with time.50 This might help explain, to some extent, the wide variation in the prevalence of aspirin resistance among different studies with similar patient populations. Even though a categoric definition of laboratory aspirin resistance seems to carry a significant predictive risk for adverse clinical events, it would be safe to infer that when seen as a continuous variable, different levels of resistance can carry a varying relationship with clinical outcomes.

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Clinical implications 

Today, one of the most important questions clinicians are called upon to answer is the extent to which laboratory resistance to aspirin signifies clinical aspirin failure? Two recent meta-analyses pooled data from a body of literature that attempted to establish an association between laboratory aspirin resistance and risk of developing a subsequent acute atherothrombotic event. In the first study, Krasopoulos et al106 assessed the rate of cardiovascular events in 2930 patients with cardiovascular disease on ASA therapy for secondary prevention. Twenty-eight percent of all participating patients were found to be resistant by a variety of laboratory assays. Out of the 20 studies pooled in this meta-analysis, compliance was ensured or adjusted for in 17. Aspirin resistance was more prevalent among men and patients with renal impairment (P < .001 and P < .03, respectively). Aspirin-resistant patients, diagnosed in the laboratory and irrespective of underlying condition or symptomatology, were at greater risk for death, acute coronary syndromes, new cerebrovascular episodes, or failure of vascular intervention (39% vs 16%; odds ratio 3.85; 95% confidence interval [CI] 3.08-4.80; P < .001). Unfortunately, not only did aspirin resistance have an adverse effect on prognosis, but this elevated risk was not attenuated by adjunct antiplatelet therapies, such as clopidogrel or tirofiban.106

Similarly, Snoep et al98 pooled data from 16 studies (n = 2296) that assessed the odds ratio of developing a recurrent acute cardiovascular episode despite aspirin use for secondary prevention. Three of the included studies were adjusted for aspirin noncompliance. In this selected-patient group, 27% were found to be resistant by a variety of laboratory assays. The pooled odds ratio for adverse clinical events in aspirin-resistant patients without any adjunctive interventional treatment, as measured by various laboratory methods, was 4.37 (95% CI 2.19-8.73; P < .001). When studies involving patients who had undergone interventional procedures after a primary cardiovascular event were included, the resulting odds ratio was 3.78 (95% CI 2.34-6.11; P < .001), in agreement with the findings of Krasopoulos et al.106 When patients were stratified by aspirin dose (≤100 mg/day; 101-299 mg/day; ≥300 mg/day), no differences were found among the various dosage groups. Both meta-analyses assumed laboratory aspirin resistance to be a categoric variable (present vs not present).

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Aspirin resistance in vascular surgery 

The majority of available studies on aspirin resistance predominately involve patients with a history of stroke and coronary artery disease, or even healthy individuals; the phenomenon has not been thoroughly explored in the vascular literature.107 Assadian et al36 reported aspirin nonresponsiveness to be 16%, as measured by PFA-100 analysis with epinephrine as a catalyst, in 86 individuals who had recently undergone CEA and were on 100 mg of aspirin daily. However, when the same individuals were assessed with flow cytometry for P-Selectin expression on platelets, all patients were found to be ASA responsive.36 An interesting demonstration of transient aspirin resistance despite chronic aspirin intake has also been demonstrated in early postoperative vascular surgery patients. Payne et al35 found that 28 out of 50 patients undergoing CEA (who had previously been on 150 mg of aspirin daily for at least 2 weeks) had significantly elevated platelet reactivity intraoperatively. This phenomenon, that was identified using light aggregometry with ARA as an agonist, was short-lived and reversed spontaneously early in the postoperative period. Similarly, peripheral vascular patients undergoing lower extremity angioplasty had a significantly higher platelet reactivity to ARA at the end of the procedure, compared to preoperatively, as reported by Webster et al,108 but this trend also self-reversed within 4 hours postoperatively. Similar transient variations have been reported in the early postprocedure periods after CABG.10 The increased platelet aggregation could not be attributed to the transient intraoperative increases of ADP, thrombin, and epinephrine due to surgical stress, because in vitro addition of inhibitors (apyrase, hirudin, and yohimbine correspondingly) failed to significantly reduce platelet response to ARA.35 Even though the clinical significance of this phenomenon in the long term is uncertain, it could explain why patients undergoing cardiovascular surgical procedures remain at risk for perioperative stroke and myocardial infarction.35 It also corroborates the notion that aspirin resistance represents an ever-changing continuum that varies from time to time even within the same individual.

Regarding the clinical relevance of aspirin resistance in patients with peripheral arterial disease, Mueller et al38 followed a group of 100 claudicants on 100 mg of aspirin daily for 18 months after undergoing elective percutaneous angioplasty. The authors demonstrated that 60% of this population demonstrated aspirin resistance by whole blood aggregometry (using collagen, ADP, and ARA as agonists). Eight of the 60 patients with ASA-resistance had reocclusions at the site of angioplasty, although none of the remaining 40 patients with normal ASA response (inhibited platelet function) had an adverse event (P = .0093). Contradicting these findings, Ziegler et al37 assessed platelet inhibition using PFA-100 (ADP was the agonist utilized) in 98 patients with documented peripheral arterial disease on 100 mg of aspirin (n = 52), 75 mg of clopidogrel (n = 34) or both (n = 12) 1 year after elective lower extremity angioplasty. Even though ASA-resistance was estimated at 9.6% (9/52), it did not correlate with a higher re-stenosis or reocclusion rate at the angioplasty sites. Contrary, clopidogrel nonresponders had a higher incidence of clinical angioplasty failure compared to responders. However, compliance was again not accounted for, patient selection was not randomized, and the small number of participants and short follow-up in this study may account for its lack of power.

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Management of aspirin-resistant individuals 

The routine laboratory evaluation of platelet reactivity is not cost-effective or justifiable in all individuals on chronic aspirin regimens.60, 109 If, however, clinical events occur while on aspirin, compliance should be assessed and optimized, polypharmacy checked, smoking cessation encouraged, and consideration be given to whether more antiplatelet agents can be added or substitute aspirin. Such agents inhibit upstream pathways of platelet activation (such as ADP receptor antagonists [thienopyridines: clopidogrel/Plavix, ticlopidine/Ticlid]), or phoshpodiesterase inhibitors (dipyridamole/Persantine), or the final common downstream pathway of platelet aggregation (such as GP IIb/IIIa receptor inhibitors [eptifibatide/Integrillin, tirofiban/Aggrastat, and abcimixab/Reopro]). Even though evidence of the efficacy of such an approach is currently conflicting and under debate,97, 110, 111, 112, 113, 114 it is these individuals that would most benefit from routine, frequent monitoring of platelet activity.

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Conclusions - future directions 

Even though laboratory-diagnosed ASA-nonresponsiveness confers a higher risk for acute thromboembolic sequelae to nonresponders, it seems to represent a continuous variable, affecting different individuals to an unpredictable extent. Routine laboratory monitoring of platelet function in all chronic aspirin-takers is not cost-effective, but should be undertaken in all individuals with clinical aspirin failure, after compliance is confirmed. For the individuals who are identified as aspirin-resistant, the importance of compliance must be stressed and smoking cessation encouraged; medications that inhibit aspirin's effectiveness should be avoided (ie, NSAIDs), and the addition of other antiplatelet drugs should be entertained.

Although consensus on a clear definition of, and laboratory criteria for, aspirin resistance needs to be established, incorporating standardized and reproducible assays, current data from other cardiovascular subspecialties should provide a springboard to stimulate research in the population of patients with peripheral vascular disease. Interest in this area among vascular surgeons should be significant, given the number of vascular patients on aspirin monotherapy for primary or secondary prevention of acute atherothrombotic episodes, or postrevascularization procedures.

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Author contributions 


Conception and design: TL, IP, GK

Analysis and interpretation: GK, IP

Data collection: GK

Writing the article: GK

Critical revision of the article: GK, IP, TL

Final approval of the article: TL

Statistical analysis: Not applicable

Obtained funding: Not applicable

Overall responsibility: GK, IP, TL

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References 

  1. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics–2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117:e25–e146
  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. Grundmann K, Jaschonek K, Kleine B, Dichgans J, Topka H. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks. J Neurol. 2003;250:63–66
  4. Alberts MJ, Bergman DL, Molner E, Jovanovic BD, Ushiwata I, Teruya J. Antiplatelet effect of aspirin in patients with cerebrovascular disease. Stroke. 2004;35:175–178
  5. McCabe DJ, Harrison P, Mackie IJ, et al. Assessment of the antiplatelet effects of low to medium dose aspirin in the early and late phases after ischaemic stroke and TIA. Platelets. 2005;16:269–280
  6. Berrouschot J, Schwetlick B, von Twickel G, et al. Aspirin resistance in secondary stroke prevention. Acta Neurologica Scandinavica. 2006;113:31–35
  7. Helgason CM, Bolin KM, Hoff JA, Winkler SR, Mangat A, Tortorice KL, et al. Development of aspirin resistance in persons with previous ischemic stroke. Stroke. 1994;25:2331–2336
  8. 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
  9. Grotemeyer KH. Effects of acetylsalicylic acid in stroke patients (Evidence of nonresponders in a subpopulation of treated patients). Thromb Res. 1991;63:587–593
  10. Zimmermann N, Wenk A, Kim U, et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation. 2003;108:542–547
  11. Yilmaz MB, Balbay Y, Caldir V, Ayaz S, Guray Y, Guray U, et al. Late saphenous vein graft occlusion in patients with coronary bypass: possible role of aspirin resistance. Thromb Res. 2005;115:25–29
  12. Buchanan MR. Biological basis and clinical implications of acetylsalicylic acid resistance. Can J Cardiol. 2006;22:149–151
  13. Buchanan MR. Acetylsalicylic acid resistance and clinical outcome–the Hobikoglu study is worth noting. Can J Cardiol. 2007;23:207–208
  14. 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
  15. Chen WH, Lee PY, Ng W, et al. Relation of aspirin resistance to coronary flow reserve in patients undergoing elective percutaneous coronary intervention. Am J Cardiol. 2005;96:760–763
  16. Zhang Y, Liang J, Zhou YJ, Yuan H, Zhang YZ, Dong L. Study on the relationship between aspirin resistance and incidence of myonecrosis after non-emergent percutaneous coronary intervention. [Article in Chinese] Zhonghua Xin Xue Guan Bing Za Zhi (Chinese J Cardiovasc Dis). 2005;33:695–699
  17. 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
  18. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003;107:2908–2913
  19. Macchi L, Christiaens L, Brabant S, et al. Resistance in vitro to low-dose aspirin is associated with platelet PlA1 (GP IIIa) polymorphism but not with C807T(GP Ia/IIa) and C-5T Kozak (GP Ibalpha) polymorphisms. J Am Coll Cardiol. 2003;42:1115–1119
  20. Christiaens L, Macchi L, Herpin D, et al. Resistance to aspirin in vitro at rest and during exercise in patients with angiographically proven coronary artery disease. Thromb Res. 2002;108:115–119
  21. 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
  22. Macchi L, Christiaens L, Brabant S, Sorel N, Allal J, Mauco G, et al. Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate. Thromb Res. 2002;107:45–49
  23. 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
  24. Friend M, Vucenik I, Miller M. Research pointers: platelet responsiveness to aspirin in patients with hyperlipidaemia. BMJ. 2003;326:82–83
  25. 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
  26. Lee PY, Chen WH, Ng W, Cheng X, Kwok JY, Tse HF, et al. Low-dose aspirin increases aspirin resistance in patients with coronary artery disease. Am J Med. 2005;118:723–727
  27. Borna C, Lazarowski E, van Heusden C, Ohlin H, Erlinge D. Resistance to aspirin is increased by ST-elevation myocardial infarction and correlates with adenosine diphosphate levels. Thromb J. 2005;3:10
  28. Andersen K, Hurlen M, Arnesen H, Seljeflot I. Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease. Thromb Res. 2002;108:37–42
  29. Hobikoglu GF, Norgaz T, Aksu H, Ozer O, Erturk M, Nurkalem Z, et al. High frequency of aspirin resistance in patients with acute coronary syndrome. Tohoku J Exp Med. 2005;207:59–64
  30. Stejskal D, Prosková J, Lacnák B, et al. [Use of assessment of aggregation of thrombocytes induced by cationic propyl gallate to estimate recurrence of cardiovascular complications]. [Article in Czech] Vnitr Lek. 2004;50:591–599
  31. Faraday N, Braunstein JB, Heldman AW, Bolton ED, Chiles KA, Gerstenblith G, 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
  32. Schwartz KA, Schwartz DE, Ghosheh K, Reeves MJ, Barber K, DeFranco A. Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction. Am J Cardiol. 2005;95:973–975
  33. 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
  34. Sane DC, McKee SA, Malinin AI, Serebruany VL. Frequency of aspirin resistance in patients with congestive heart failure treated with antecedent aspirin. Am J Cardiol. 2002;90:893–895
  35. Payne DA, Jones CI, Hayes PD, Webster SE, Ross Naylor A, Goodall AH. Platelet inhibition by aspirin is diminished in patients during carotid surgery: a form of transient aspirin resistance?. Thromb Haemost. 2004;92:89–96
  36. Assadian A, Lax J, Meixner-Loicht U, Hagmüller GW, Bayer PM, Hübl W. Aspirin resistance among long-term aspirin users after carotid endarterectomy and controls: flow cytometric measurement of aspirin-induced platelet inhibition. J Vasc Surg. 2007;45:1142–1147discussion 1147
  37. Ziegler S, Maca T, Alt E, Speiser W, Schneider B, Minar E. Monitoring of antiplatelet therapy with the PFA-100 in peripheral angioplasty patients. Platelets. 2002;13:493–497
  38. 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
  39. Malinin A, Spergling M, Muhlestein B, Steinhubl S, Serebruany V. Assessing aspirin responsiveness in subjects with multiple risk factors for vascular disease with a rapid platelet function analyzer. Blood Coagul Fibrinolysis. 2004;15:295–301
  40. Wang JC, Aucoin-Barry D, Manuelian D, et al. Incidence of aspirin nonresponsiveness using the Ultegra Rapid Platelet Function Assay-ASA. Am J Cardiol. 2003;92:1492–1494
  41. Marshall PW, Williams AJ, Dixon RM, Growcott JW, Warburton S, Armstrong J, et al. A comparison of the effects of aspirin on bleeding time measured using the Simplate method and closure time measured using the PFA-100, in healthy volunteers. Br J Clin Pharmacol. 1997;44:151–155
  42. Hillarp A, Lethagen S, Mattiasson I. Aspirin resistance is not a common biochemical phenotype explained by unblocked cyclooxygenase-1 activity. J Thromb Haemost. 2003;1:196–197
  43. Jack DB. One hundred years of aspirin. Lancet. 1997;350:437–439
  44. The Royal Society of London. An account of the success of the bark of the willow in the cure of agues (In a letter to the Right Honourable George Earl of Macclesfield, President of R. S. from the Rev. Mr. Edmund Stone, of Chipping-Norton in Oxfordshire). Philos Trans R Soc Lond. 1763;53:195–200
  45. Sneader W. The discovery of aspirin: a reappraisal. BMJ. 2000;321:1591–1594
  46. Craven LL. Experiences with aspirin (Acetylsalicylic acid) in the nonspecific prophylaxis of coronary thrombosis. Miss Valley Med J. 1953;75:38–44
  47. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008;359:938–949
  48. Palabrica T, Lobb R, Furie BC, et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature. 1992;359:848–851
  49. Roth GJ, Calverley DC. Aspirin, platelets, and thrombosis: theory and practice. Blood. 1994;83:885–898
  50. Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet. 2006;367:606–617
  51. Brunton L, Lazo J, Parker K. Goodman & Gilman's The Pharmacological Basis of Therapeutics. McGraw-Hill Professional; 2005;
  52. Hankey GJ, Eikelboom JW. Antiplatelet drugs. Med J Aust. 2003;178:568–574
  53. Bhatt DL, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov. 2003;2:15–28
  54. Homoncik M, Jilma B, Hergovich N, Stohlawetz P, Panzer S, Speiser W. Monitoring of aspirin (ASA) pharmacodynamics with the platelet function analyzer PFA-100. Thromb Haemost. 2000;83:316–321
  55. Serebruany VL, Malinin AI, Oshrine BR, Sane DC, Takserman A, Atar D, et al. Lack of uniform platelet activation in patients after ischemic stroke and choice of antiplatelet therapy. Thromb Res. 2004;113:197–204
  56. Hézard N, Metz D, Nazeyrollas P, Droullé C, Potron G, Nguyen P. PFA-100 and flow cytometry: can they challenge aggregometry to assess antiplatelet agents, other than GPIIbIIIa blockers, in coronary angioplasty?. Thromb Res. 2002;108:43–47
  57. Michelson AD. Methods for the measurement of platelet function. Am J Cardiol. 2009;103(3 Suppl):20A–26A
  58. Schwartz KA, Schwartz DE, Barber K, Reeves M, De Franco AC. Non-compliance is the predominant cause of aspirin resistance in chronic coronary arterial disease patients. J Transl Med. 2008;6:46
  59. Johnson SB. Methodological issues in diabetes research (Measuring adherence). Diabetes Care. 1992;15:1658–1667
  60. Shantsila E, Lip GY. ‘Aspirin resistance’ or treatment non-compliance: which is to blame for cardiovascular complications?. J Transl Med. 2008;6:47
  61. Carney RM, Freedland KE, Eisen SA, Rich MW, Skala JA, Jaffe AS. Adherence to a prophylactic medication regimen in patients with symptomatic versus asymptomatic ischemic heart disease. Behav Med. 1998;24:35–39
  62. Dalen JE. Aspirin resistance: is it real? (Is it clinically significant?). Am J Med. 2007;120:1–4
  63. Dalen JE. Is aspirin resistance due to noncompliance?. Arch Intern Med. 2008;168:550;author reply 550
  64. Maclouf J, Folco G, Patrono C. Eicosanoids and iso-eicosanoids: constitutive, inducible and transcellular biosynthesis in vascular disease. Thromb Haemost. 1998;79:691–705
  65. Santos MT, Moscardó A, Vallés J, et al. Participation of tyrosine phosphorylation in cytoskeletal reorganization, alpha(IIb)beta(3) integrin receptor activation, and aspirin-insensitive mechanisms of thrombin-stimulated human platelets. Circulation. 2000;102:1924–1930
  66. Gerschutz GP, Bhatt DL The Clopidogrel in Unstable Angina to Prevent Recurrent Events study. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study: to what extent should the results be generalizable?. Am Heart J. 2003;145:595–601
  67. Kawasaki T, Ozeki Y, Igawa T, Kambayashi J. Increased platelet sensitivity to collagen in individuals resistant to low-dose aspirin. Stroke. 2000;31:591–595
  68. Furman MI, Benoit SE, Barnard MR, et al. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol. 1998;31:352–358
  69. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets (I. Acetylation of a particulate fraction protein). J Clin Invest. 1975;56:624–632
  70. Bojesen SE, Juul K, Schnohr P, Tybjaerg-Hansen A, Nordestgaard BG Copenhagen City Heart Study. Platelet glycoprotein IIb/IIIa Pl(A2)/Pl(A2) homozygosity associated with risk of ischemic cardiovascular disease and myocardial infarction in young men: the Copenhagen City Heart Study. J Am Coll Cardiol. 2003;42:661–667
  71. Michelson AD, Furman MI, Goldschmidt-Clermont P, et al. Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists. Circulation. 2000;101:1013–1018
  72. Undas A, Brummel K, Musial J, Mann KG, Szczeklik A. Pl(A2) polymorphism of beta(3) integrins is associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury. Circulation. 2001;104:2666–2672
  73. Andrioli G, Minuz P, Solero P, Pincelli S, Ortolani R, Lussignoli S, et al. Defective platelet response to arachidonic acid and thromboxane A(2) in subjects with Pl(A2) polymorphism of beta(3) subunit (glycoprotein IIIa). Br J Haematol. 2000;110:911–918
  74. Samani NJ, Lodwick D. Glycoprotein IIIa polymorphism and risk of myocardial infarction. Cardiovasc Res. 1997;33:693–697
  75. Weiss EJ, Bray PF, Tayback M, et al. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med. 1996;334:1090–1094
  76. Mikkelsson J, Perola M, Laippala P, Penttilä A, Karhunen PJ. Glycoprotein IIIa Pl(A1/A2) polymorphism and sudden cardiac death. J Am Coll Cardiol. 2000;36:1317–1323
  77. Schönbeck U, Sukhova GK, Graber P, Coulter S, Libby P. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol. 1999;155:1281–1291
  78. Patrignani P, Sciulli MG, Manarini S, Santini G, Cerletti C, Evangelista V. COX-2 is not involved in thromboxane biosynthesis by activated human platelets. J Physiol Pharmacol. 1999;50:661–667
  79. Rocca B, Secchiero P, Ciabattoni G, et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci U S A. 2002;99:7634–7639
  80. Weber AA, Zimmermann KC, Meyer-Kirchrath J, Schrör K. Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance. Lancet. 1999;353:900
  81. Cipollone F, Rocca B, Patrono C. Cyclooxygenase-2 expression and inhibition in atherothrombosis. Arterioscler Thromb Vasc Biol. 2004;24:246–255
  82. Pulcinelli FM, Pignatelli P, Celestini A, Riondino S, Gazzaniga PP, Violi F. Inhibition of platelet aggregation by aspirin progressively decreases in long-term treated patients. J Am Coll Cardiol. 2004;43:979–984
  83. Burch JW, Stanford N, Majerus PW. Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest. 1978;61:314–319
  84. Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest. 1982;69:1366–1372
  85. FitzGerald GA, Oates JA, Hawiger J, Maas RL, Roberts LJ, Lawson JA, et al. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest. 1983;71:676–688
  86. De Caterina R, Giannessi D, Boem A, et al. Equal antiplatelet effects of aspirin 50 or 324 mg/day in patients after acute myocardial infarction. Thromb Haemost. 1985;54:528–532
  87. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):234S–264S
  88. Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Baggish JS, Bhatt DL, et al. Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials. Am J Cardiol. 2005;95:1218–1222
  89. Helgason CM, Tortorice KL, Winkler SR, Penney DW, Schuler JJ, McClelland TJ, et al. Aspirin response and failure in cerebral infarction. Stroke. 1993;24:345–350
  90. Hurlen M, Seljeflot I, Arnesen H. The effect of different antithrombotic regimens on platelet aggregation after myocardial infarction. Scand Cardiovasc J. 1998;32:233–237
  91. Abaci A, Yilmaz Y, Caliskan M, Bayram F, Cetin M, Unal A, et al. Effect of increasing doses of aspirin on platelet function as measured by PFA-100 in patients with diabetes. Thromb Res. 2005;116:465–470
  92. von Pape KW, Strupp G, Bonzel T, Bohner J. Effect of compliance and dosage adaptation of long term aspirin on platelet function with PFA-100 in patients after myocardial infarction. Thromb Haemost. 2005;94:889–891
  93. Dippel DW, Van Kooten F, Leebeek FW, van Vliet HH, Mehicevic A, Li SS, et al. What is the lowest dose of aspirin for maximum suppression of in vivo thromboxane production after a transient ischemic attack or ischemic stroke?. Cerebrovasc Dis. 2004;17:296–302
  94. Hart RG, Leonard AD, Talbert RL, Pearce LA, Cornell E, Bovill E, et al. Aspirin dosage and thromboxane synthesis in patients with vascular disease. Pharmacotherapy. 2003;23:579–584
  95. Cerletti C, Dell'Elba G, Manarini S, et al. Pharmacokinetic and pharmacodynamic differences between two low dosages of aspirin may affect therapeutic outcomes. Clin Pharmacokinet. 2003;42:1059–1070
  96. Tohgi H, Konno S, Tamura K, Kimura B, Kawano K. Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin. Stroke. 1992;23:1400–1403
  97. Quinn MJ, Aronow HD, Califf RM, et al. Aspirin dose and six-month outcome after an acute coronary syndrome. J Am Coll Cardiol. 2004;43:972–978
  98. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Huisman MV. 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
  99. Akopov SS, Grigorian GS, Gabrielian ES. Dose-dependent aspirin hydrolysis and platelet aggregation in patients with atherosclerosis. J Clin Pharmacol. 1992;32:133–135
  100. Pappas JM, Westengard JC, Bull BS. Population variability in the effect of aspirin on platelet function (Implications for clinical trials and therapy). Arch Pathol Lab Med. 1994;118:801–804
  101. Williams FM, Mutch EM, Nicholson E, Wynne H, Wright P, Lambert D, et al. Human liver and plasma aspirin esterase. J Pharm Pharmacol. 1989;41:407–409
  102. Hung J, Lam JY, Lacoste L, Letchacovski G. Cigarette smoking acutely increases platelet thrombus formation in patients with coronary artery disease taking aspirin. Circulation. 1995;92:2432–2436
  103. Alexander JH, Harrington RA, Tuttle RH, et al. Prior aspirin use predicts worse outcomes in patients with non-ST-elevation acute coronary syndromes (PURSUIT Investigators. Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy). Am J Cardiol. 1999;83:1147–1151
  104. Santopinto J, Gurfinkel EP, Torres V, et al. Prior aspirin users with acute non-ST-elevation coronary syndromes are at increased risk of cardiac events and benefit from enoxaparin. Am Heart J. 2001;141:566–572
  105. Buchanan MR, Brister SJ. Individual variation in the effects of ASA on platelet function: implications for the use of ASA clinically. Can J Cardiol. 1995;11:221–227
  106. Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ. 2008;336:195–198
  107. Lynch TG, Pipinos II. Invited Commentary. J Vasc Surg. 2007;45:1147
  108. Webster SE, Payne DA, Jones CI, Hayes PD, Bell PR, Goodall AH, et al. Anti-platelet effect of aspirin is substantially reduced after administration of heparin during carotid endarterectomy. J Vasc Surg. 2004;40:463–468
  109. 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
  110. Wong S, Morel-Kopp MC, Chen Q, Appleberg M, Ward CM, Lewis DR. Overcoming aspirin resistance: increased platelet inhibition with combination aspirin and clopidogrel and high dose aspirin therapy in aspirin resistant patients with peripheral vascular disease. Thromb Haemost. 2006;95:1042–1043
  111. [No authors listed] A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) (CAPRIE Steering Committee). Lancet. 1996;348:1329–1339
  112. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358:527–533
  113. Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288:2411–2420
  114. Bhatt DL, Topol EJ Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance Executive Committee. Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Am Heart J. 2004;148:263–268

 Competition of interest: none.

 The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a competition of interest.

PII: S0741-5214(09)01334-2

doi:10.1016/j.jvs.2009.06.023

Journal of Vascular Surgery
Volume 50, Issue 6 , Pages 1500-1510, December 2009

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