STATE-OF-THE-ART PAPER
The Role of Aspirin in Cardiovascular PreventionImplications of Aspirin Resistance
Armen Yuri Gasparyan, MD, PhD,
Timothy Watson, MRCP and
Gregory Y.H. Lip, MD, FRCP*
Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, United Kingdom.
Manuscript received September 13, 2007;
revised manuscript received October 19, 2007,
accepted November 10, 2007.
* Reprint requests and correspondence: Prof. Gregory Y. H. Lip, Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, United Kingdom. (Email: g.y.h.lip{at}bham.ac.uk).
 |
Abstract
|
|---|
Aspirin is well recognized as an effective antiplatelet drug for secondary prevention in subjects at high risk of cardiovascular events. However, most patients receiving long-term aspirin therapy still remain at substantial risk of thrombotic events due to insufficient inhibition of platelets, specifically via the thromboxane A2 pathway. Although the exact prevalence is unknown, estimates suggest that between 5.5% and 60% of patients using this drug may exhibit a degree of "aspirin resistance," depending upon the definition used and parameters measured. To date, only a limited number of clinical studies have convincingly investigated the importance of aspirin resistance. Of these, few are of a sufficient scale, well designed, and prospective, with aspirin used at standard doses. Also, most studies do not sufficiently address the issue of noncompliance to aspirin as a frequent, yet easily preventable cause of resistance to this antiplatelet drug. This review article provides a comprehensive overview of aspirin resistance, discussing its definition, prevalence, diagnosis, and therapeutic approaches. Moreover, the clinical implications of aspirin resistance are explored in various cardiovascular disease states, including diabetes mellitus, hypertension, heart failure, and other similar disorders where platelet reactivity is enhanced.
|
Abbreviations and Acronyms
| | ACE = angiotensin-converting enzyme | | ADP = adenosine diphosphate | | CI = confidence interval | | COX = cyclooxygenase | | CRP = C-reactive protein | | MI = myocardial infarction | | NO = nitric oxide | | RPFA = rapid platelet function assay |
|
The fascinating history of aspirin-like remedies traces back to antiquity. The Assyrians and the Egyptians were well aware of the analgesic effects of a decoction of myrtle or willow leaves for joint pain (1). Since the times of Hippocrates, Celsus, Pliny the Elder, Dioscorides, and Galen, remedies made from willow bark were used as antipyretic and antirheumatic therapies (2). In 1838, the Italian chemist, Rafaelle Piria discovered the active ingredient in willow bark—salicylic acid (3). However, it was not until some 60 years later when in 1897, Felix Hoffman, who worked for the Bayer pharmaceutical company in Germany, synthesized the acetylated form of salicylic acid, which was named "aspirin," and became the most widely used drug of all time (4). Aspirin differed markedly from previous forms of salicylic acid, with improved tolerability and reduced gastrointestinal side effects, and remains widely used as both an anti-inflammatory and antirheumatic drug.
A new era of aspirin usage began in 1971 when Sir John Vane demonstrated that the main mechanism of action was the inhibition of prostaglandin synthesis (5). The critical importance of this discovery was underlined in 1982 when Vane was awarded the Nobel Prize for Medicine (1). Subsequent clinical and experimental studies have demonstrated that low-dose aspirin irreversibly acetylates a serine residue at position 530 on the cyclooxygenase-1 (COX-1) enzyme in platelets, thus blocking synthesis of prostaglandin G2/H2 (Fig. 1). This reaction is the first in a series that allows transformation of arachidonic acid into the potent platelet agonist, thromboxane A2, thereby leading to the beneficial clinical effect of aspirin in patients with coronary artery disease and stroke (6–9).
The importance of aspirin therapy in this setting is sealed by a large meta-analysis from the Antithrombotic Trialists' Collaboration (287 randomized trials of antiplatelet therapy of patients at high risk of occlusive vascular events), which demonstrated a 32% reduction of nonfatal myocardial infarction (MI), nonfatal stroke, and vascular death in patients treated with 75 to 150 mg aspirin daily (10). Despite such strong evidence, it is increasingly appreciated that some patients still fail to respond adequately to aspirin therapy. This is usually seen by the occurrence of further clinical (thrombotic) events despite aspirin treatment in "usual" prophylactic dosages. Such "aspirin resistance" has also been defined in the laboratory setting by the failure of aspirin to fully inhibit platelet aggregation.
This review provides an overview on the importance of aspirin therapy in primary and secondary prevention of vascular disease and explores the purported role of aspirin resistance and the implications of this for everyday clinical practice.
|
Search Criteria
|
|---|
We performed a comprehensive search of electronic bibliographic databases (e.g., MEDLINE, EMBASE, DARE) for English-language sources using key words related to aspirin use in randomized clinical trials. In addition, several relevant full-text review articles were identified from ProQuest Medical Library. We hand searched bibliographies for important articles and reviewed abstracts from major conferences. We also searched the open databases of the Cochrane Collaboration and the Clinical Trials database for other relevant studies.
|
Aspirin in the Prevention of Vascular Disease
|
|---|
The role of aspirin in primary prevention of vascular disease has been investigated in 6 randomized controlled trials (11–16) and in several meta-analyses (17,18), as summarized in Table 1. Although 4 of these trials clearly indicate the importance of aspirin for primary prevention (11,13–15), a meta-analysis of all trials (n = 95,456 participants, 54% women) for an average follow-up period of 6.4 years surprisingly did not find a significant reduction in the risk of stroke, cardiovascular, or all-cause mortality (17,18), presumably because the majority of patients included were, in fact, at low risk for vascular disease.
Among the randomized trials, the Physicians' Health study (11) merits special attention. This prospective study not only demonstrated the important efficacy of aspirin in reducing vascular events, but also explored the link between chronic inflammation and atherothrombosis. The investigators found that levels of C-reactive protein (CRP) (a marker of inflammation) were predictive of future MI and stroke, and that the greatest and most statistically significant reduction in risk of a first MI associated with aspirin use was observed among men with baseline CRP levels in the highest quartile.
In contrast to the conflicting data for primary prevention, the majority of studies of aspirin for secondary prevention have clearly shown the positive efficacy of this drug. One important example is the ISIS-2 (Second International Study of Infarct Survival) study, where the benefits of early administration of 162.5 mg of aspirin after acute MI were clear. After 35 days follow-up from the index event, a 9.4% death rate was observed in the aspirin group compared with 12.0% in the placebo arm (risk ratio 0.78; 95% confidence interval [CI] 0.71 to 0.85; p < 0.0001) (19).
The inequity in efficacy for aspirin between primary and secondary prevention trials and the apparent failure of aspirin to suppress further events in some patients raises important questions. 1) In which patient group(s) does aspirin therapy have the greatest efficacy? 2) Which factors are implicated in aspirin treatment failure (aspirin resistance)? 3) Are laboratory assays available to reliably identify patients who will not sufficiently respond to aspirin? 4) Is combined antiplatelet therapy more advantageous than aspirin alone?
|
"Aspirin Resistance" and Its Implications
|
|---|
There has been a staggering increase in the volume of literature addressing the issue of so-called "aspirin resistance" in recent years. Terminology and definitions vary widely, some based on clinical observations and other based upon measurement of various laboratory parameters, defined from both in vivo and in vitro studies.
The term "aspirin resistance" has various synonyms, including "aspirin nonresponsiveness," "aspirin treatment failure," and "inadequate aspirin efficacy," but has also been sometimes defined as "biochemical or laboratory aspirin resistance" (20,21). Estimates of the prevalence of aspirin resistance vary widely (5.5% to 60%), reflecting the diversity of various laboratory assays and confounding from the broad range of disease states investigated (22–27).
To the practicing clinician, a definition and diagnosis of aspirin resistance based on clinical assessment of treatment outcomes (i.e., adverse vascular events) would seem preferable. Nevertheless, the major limitation to this approach is that it relies upon a retrospective review of clinical events. For this reason, most researchers are increasingly advocating the application of various laboratory tests.
|
Laboratory Assessment of Aspirin Resistance
|
|---|
Light or optical aggregometry, which is generally considered the "gold standard" of platelet function assessment, is the most widely used technique for defining aspirin resistance. The technique is based on the increase in light transmission through platelet-rich plasma as a result of aggregation of platelets and formation of clumps in response to various agonists. Although numerous agonists (e.g., arachidonic acid, adenosine diphosphate [ADP], epinephrine, collagen, thrombin) can be used, the most specific for detection of aspirin resistance appears to be arachidonic acid, which induces platelet aggregation through the thromboxane A2 pathway. Using this method, the most widely accepted definition of aspirin resistance is  20% platelet aggregation with 1 mg/ml arachidonic acid and 70% aggregation with 10 µmol/l ADP (28).
Optical aggregometry generally correlates well with clinical outcomes (e.g., death, cardiovascular, and cerebrovascular events), but there is often a lack of agreement with other measures of platelet function; for example, the Platelet Function Analyzer-100 (PFA-100) (Dade Behring, Leiderbach, Germany) (29). Besides, optical aggregometry has several other limitations, including the necessity to run the assay rapidly (usually within 1 to 3 h of blood collection) and a dependence upon operator and interpreter experience. In addition, difficulties in reproducing and comparing results obtained in the same and different laboratories are frequently reported (30). As an ex vivo test, optical aggregometry neglects to assess several important factors, such as the interactions between platelets, erythrocytes, neutrophils, and monocytes and also the high shear stress induced by vascular injury.
To overcome some of these limitations, the PFA-100 device (Dade Behring) was developed (31). This allows measurement of the closure time of a microscopic aperture in a membrane/cartridge coated with collagen/epinephrine or collagen/ADP using whole blood anticoagulated with sodium citrate. The system simulates injured artery, high shear stress conditions, and operates in the presence of erythrocytes. Thus, platelet function is assessed by the time taken to form a platelet plug occluding the aperture. Using this test, aspirin resistance is generally defined as a closure time for a collagen/epinephrine cartridge of <164 s despite regular aspirin intake.
What are the advantages of the PFA-100? The device is simple to use and requires only a small volume of blood (800 µl). The test is also quick and has good sensitivity and reproducibility. Nonetheless, there are several limitations, including dependence upon plasma von Willebrand factor and hematocrit, the necessity to test blood samples within 3 to 4 h after blood collection, and expense: all factors that restrict the widespread and practical applicability of this test.
Another point-of-care, easy-to-use, and rapid test for defining aspirin resistance is the VerifyNow-Aspirin (the Ultegra Rapid Platelet Function Assay, Accumetrics Inc., San Diego, California), which is a turbidimetric-based optical detection system for measuring platelet-induced aggregation (32). The VerifyNow-Aspirin assay correlates well with optical aggregometry, and uses an aspirin cartridge with fibrinogen-coated beads and a platelet activator (metallic cations, propyl gallate, arachidonic acid) to stimulate the COX-1 pathway and to measure aspirin reaction units (32). The most important limitation of this test relates to its diagnostic criteria, as these were set in comparison with optical aggregation in response to adrenaline, after only a single 325-mg dose of aspirin.
Other laboratory measures of aspirin resistance are also available. These include in vivo measurement of thromboxane A2 pathway end products, such as serum thromboxane B2 (33) and urinary 11-dehydrothromboxane B2 (34). Neither test specifically reflects platelet activity, but instead may reflect the contribution of monocytes/macrophages to thromboxane A2 synthesis and also the COX-2 linked pathway of arachidonic acid, which is only partially blocked by aspirin. In addition, ex vivo platelet activation during blood sample collection, storage, and processing may also interfere with the results of these tests. Urinary 11-dehydrothromboxane B2 concentrations are also highly dependent on renal production of this metabolite, further complicating interpretation of this test. Nevertheless, as a relatively straightforward and inexpensive in vivo test that can be performed on stored samples, the measurement of urinary 11-dehydrothromboxane B2 is frequently used in large trials on aspirin resistance (34,35).
Measurement of platelet membrane-bound P-selectin expression by flow cytometry and the level of soluble P-selectin in plasma by enzyme-linked immunoadsorbent assay has also been employed in some studies of platelet activation in disease states (22,36). However, the fact that this molecule may be expressed on cells other than platelets has resulted in conflicting data when this marker is used to assess aspirin efficacy (37,38).
|
How Prevalent Is Aspirin Resistance?
|
|---|
Many of the tests proposed to define the prevalence of aspirin resistance lack sensitivity, specificity, and reproducibility. Indeed, a recent systematic review by Hovens et al. (39) reiterated this point, emphasizing that the prevalence of aspirin resistance as defined by each test varied widely: the lowest figure seen with optical aggregometry using arachidonic acid (6%; 95% CI 0% to 12%) and the highest prevalence with the PFA-100 analyzer (26%; 95% CI 21% to 31%).
Given the complexity of pathways of platelet activation and poor correlation between assays, some have advocated using a combination of criteria for aspirin resistance based on multiple parameters. In a recent study by Sane et al. (40), for example, aspirin resistance was considered to be present if 4 of the following 5 criteria were met: collagen-induced aggregation >70%; ADP-induced aggregation >60%; whole-blood aggregation >18 Ohm; expression of glycoprotein IIa/IIIa >220 log mean fluorescence units; or P-selectin membrane receptor positivity >8%. Even with this (very) strict definition, Sane et al. (40) reported that the incidence of aspirin resistance in heart failure patients was shown to be 55%. In contrast, another study screening for aspirin resistance in patients receiving low-dose aspirin after transient ischemic attack or ischemic stroke found the prevalence of the aspirin resistance to be 17% using the VerifyNow-Aspirin assay, 22% by the PFA-100, 5% by optical aggregometry, and only 2% by the combination of these tests (31).
|
Prospective Studies
|
|---|
Although there are numerous studies of aspirin resistance, only 4 studies to date are of sufficiently large scale and well-designed, using doses of aspirin frequently prescribed in clinical practice (34,41–43) (Table 2). In each, the sample size was >100, and follow-up was for at least 1 year. Such study design is important when assessing the relative prognostic value of each test used to define aspirin resistance.
In these prospective studies, the lowest prevalence of aspirin resistance was defined using aggregometry (between 5.2% and 8%) (41,42), while the PFA-100 analyzer yielded the highest frequency of aspirin resistance (22.2%) (43). The number of major adverse events during the follow-up period was relatively low in each study, and, thus, it became inappropriate to draw firm conclusions on the significance of aspirin resistance from these studies. Furthermore, each was limited by failure to correct for confounding factors (particularly age and gender) and the failure to assess adherence to aspirin by measurement of serum salicylate levels. Certainly, it is possible and plausible that hypertension, diabetes, peripheral vascular disease, smoking, and various other confounding factors may contribute to aspirin resistance, while also enhancing vascular risk (and thereby often necessitating aspirin therapy) in their own right. Such potential confounders clearly need to be elucidated, as does the effect of race and gender on the efficacy of aspirin therapy.
Recently, researchers have even highlighted the dynamic nature of aspirin resistance, the extent of which may vary, as blood pressure and various biochemical markers do, throughout the day and with sickness and health (24,25,44). Consequently, the value of a single point estimate measure of aspirin resistance at baseline only is questionable, and certainly more advanced study designs are required.
|
Possible Causes of Aspirin Resistance
|
|---|
As the main antiplatelet mechanism of aspirin relates to irreversible inhibition of COX-1 enzyme in mature platelets, the possible causes of aspirin resistance might be divided into 2 main groups: those related to the COX-1 pathway of thromboxane A2 production and those unrelated (Table 3).
In a series of small studies, an interesting hypothesis of the PlA polymorphism (Leu33Pro, PlA1/A2) of the platelet membrane glycoprotein IIIa gene as the main genetic background of biological aspirin resistance has been suggested (45–47). Carriers of the PlA2 allele, particularly in the homozygous state, have been considered more resistant to the antiplatelet action of aspirin and, thus, may require treatment with alternative or additional agent(s).
Unfortunately, no prospective studies have investigated the prognostic significance of glycoprotein IIIa gene polymorphisms, and only conflicting data are available (48,49). Also, there is speculation that polymorphism of COX-1 gene, overexpression of COX-2 messenger ribonucleic acid on platelets, and endothelial cells and polymorphism of platelet glycoprotein Ia/IIa collagen-receptor gene might be equally plausible causes for aspirin resistance (50). Clearly, more research is required to address these factors.
Based on a number of large trials and meta-analyses (10), low doses of aspirin (75 to 150 mg/day) are comparatively safe and sufficient to inhibit platelet COX-1 and are as effective in preventing vascular events as higher aspirin doses (500 to 1,500 mg/day). In some patients, the failure to suppress platelet COX-1 may be due to an inadequate dosage and reduced bioavailability of aspirin. In some cases, this may well relate to poor patient adherence (compliance), concurrent administration of nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, indomethacin) and COX-2 inhibitors (which may compete with aspirin for platelet COX-1), or even a reduced absorption (or increased metabolism) of aspirin (24,51,52). Such concerns have been highlighted in a recent meta-analysis of 6 studies focusing either on nonadherence or premature discontinuation of aspirin in over 50,000 patients at high risk of coronary artery disease, where a 3-fold increased risk of cardiac events (odds ratio 3.14; 95% CI 1.75 to 5.61; p = 0.0001) was related to nonadherence or the unjustified withdrawal of aspirin (53).
Nonetheless, poor compliance is not unique to aspirin and occurs to a certain extent with all prescribed medications. Various factors that increase nonadherence rates have been identified and include polypharmacy (4 or more drugs, including aspirin and coadministration of other nonsteroidal anti-inflammatory drugs), poor patient understanding of the benefits of antiplatelet therapy, and side effects (54). Obviously, to overcome nonadherence to aspirin, it is quite important to educate patients about the mechanism of action of this agent, as well as its difference from common cardiovascular drugs (e.g., angiotensin-converting enzyme [ACE] inhibitors, beta-blockers, calcium antagonists, antidiabetic drugs, and statins), which demonstrate their effect within relatively short periods of time, and in clinical practice, their effects can be easily quantified (e.g., blood pressure, heart rate, glucose, and lipid levels). To further explore the role of nonadherence and its relevance to the studies of aspirin resistance, Schwartz et al. (55) tested platelet function by arachidonic acid-induced light aggregometry in patients with a prior MI. Measurements were taken while patients were receiving their usual daily aspirin, after stopping aspirin for 7 days, and then 2 h after ingestion of aspirin, 325 mg; at the first time point, laboratory nonresponsiveness to aspirin was observed in 17 patients (9%), whereas at the third time point only in 1 patient (0.5%).
Age, weight, and intake of proton pump inhibitors may also reduce the bioavailability of low-dose aspirin, mainly due to increased inactivation of acetylsalicylic acid by gastrointestinal mucosal esterases and reduced absorption of active acetylsalicylic acid (24). Although low-dose aspirin may potentially be a cause of apparent aspirin resistance through reduced absorption, the use of higher doses of aspirin seems unjustifiable and is outweighed by an increased risk of gastrointestinal bleeding (56). However, in conditions accompanied by increased platelet turnover (e.g., acute coronary syndromes, coronary artery bypass grafting and other surgical procedures, acute or chronic infection, inflammation), a temporary increase of aspirin dose seems reasonable, albeit unproven. Under these circumstances, low-dose aspirin, given its short half-life (15 to 20 min), is unable to inhibit COX-1 in platelets rapidly released into the circulation (57–60). However, although COX-1-dependent mechanisms are suggested to be responsible for aspirin resistance in these conditions, it is more likely that more complex pathways and proinflammatory/thrombogenic molecules are also involved. Circumstantial evidence for this claim is available as aspirin resistance (as defined by PFA-100) is twice as common in acute coronary syndromes complicated by pneumonia compared with those cases without infectious complications (90% vs. 46%) (60). In addition, there appears to be an independent association between CRP and aspirin resistance in these patients.
Thus, in conditions that are associated with both infection and inflammation, nonplatelet sources of thromboxane A2 production (e.g., monocytes, macrophages, endothelial cells) and up-regulation of the COX-2 enzyme coupled with increased levels of F2-isoprostanes may lead to uncontrolled thromboxane synthesis. Such COX-1-independent mechanisms are especially relevant to patients with diabetes mellitus (61–63), hyperlipidemia (64), smoking (65), and heart failure (66–68), all of which are associated with augmented lipid peroxidation of arachidonic acid and consequent overproduction of isoprostanes. Again, these issues have implications for defining aspirin resistance, as well as its assessment.
Studies defining the causes of aspirin resistance suggest that the mechanistic approach to this phenomenon have relied largely on COX-1 pathway studies, and the use of "more specific" laboratory tests employing arachidonic acid-induced platelet activation and aggregation is often far from being pathophysiologically justifiable, pragmatic, or practical (69,70). To predict the risk of atherothrombotic events in patients on aspirin, a comprehensive approach to measure residual platelet reactivity caused by the arachidonic acid pathway (and perhaps, multiple pathways), which are "nonblocked" by aspirin, seems more important, albeit significantly less straightforward and poorly explored (71) (Fig. 2).
View larger version (42K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2 Role of COX-1–Related and Nonrelated Mechanisms of Aspirin Resistance in Several Clinical Conditions
Figure illustration by Rob Flewell. COX = cyclooxygenase; CRP = C-reactive protein.
|
|
|
Aspirin Resistance in Cardiovascular Disorders
|
|---|
Heart failure.
Many of the complications associated with heart failure are thrombus related. Given the high mortality and morbidity associated with heart failure, aspirin resistance may play a role. To date, only 1 study has found a high prevalence of aspirin resistance in heart failure. In this study, Sane et al. (40) examined 88 patients with congestive heart failure treated with aspirin (325 mg/day) for more than 1 month and found aspirin resistance to be present in as much as 55% of patients.
Is this clinically significant? Indeed, there is conflicting evidence regarding the benefits of aspirin in reducing the high incidence of vascular events in patients with chronic heart failure (72), and aspirin may possibly attenuate the efficacy of ACE inhibitors in heart failure patients (73). In 1 large study of 24,012 patients age 65 years or older with heart failure secondary to coronary artery disease, those taking aspirin (54%) only had modestly lower risk of death (risk ratio 0.94; 95% CI 0.90 to 0.99) and were relatively free of a negative interaction with ACE inhibitors (74). Other observational studies (e.g., patients with ischemic cardiomyopathy, age over 75 years) found no difference in all-cause mortality and hospitalization within 1 year of index hospitalization regardless of aspirin usage (75).
To date, the efficacy of aspirin in heart failure has been assessed in 3 controlled prospective trials. In the WASH (Warfarin/Aspirin Study in Heart failure) trial, patients with heart failure were recruited and randomized to placebo, aspirin 300 mg/day, or warfarin. Within the follow-up period (27 ± 1 months), patients taking aspirin had more hospitalizations due to heart failure (p = 0.044). However, there was no difference in primary outcomes of the study (death, nonfatal MI, or stroke) between the 3 study arms (76). In a larger trial, the WATCH (Warfarin and Antiplatelet Therapy in Chronic Heart failure) trial, patients were randomized to aspirin (162 mg), clopidogrel, or warfarin (77). Unfortunately, this trial was underpowered and terminated prematurely due to poor patient recruitment. Again, there was no detectable difference in primary outcome between 3 arms, but hospitalization rate in the aspirin arm was significantly higher (22.2% vs. 16.1% and 18.3% for aspirin, warfarin, and clopidogrel, respectively; p = 0.01). Finally, the HELAS (Heart Failure Long-term Antithrombotic Study) was initially aimed at recruiting 6,000 patients with chronic heart failure of New York Heart Association functional class II to IV (78). Patients were randomized to aspirin 325 mg daily, warfarin, or placebo and followed for 2 years to determine the rate of thromboembolic, hemorrhagic, and lethal events. Again, this trial was terminated prematurely because of recruitment difficulties, and only 197 patients with left ventricular ejection fraction <35% were enrolled, with no significant difference shown in the incidence of MI, hospitalization, heart failure decompensation, death, and hemorrhage rate between the groups (79).
Such data have led to the conclusion that aspirin therapy may possibly attenuate the efficacy of ACE inhibitors and, therefore, explain the increased hospitalization rate in heart failure patients taking aspirin in these trials (73). Given the paucity of evidence for use of aspirin in heart failure and the apparent high rate of aspirin resistance, further prospective trials are required in this setting (72). The WARCEF (Warfarin versus Aspirin in patients with reduced Cardiac Ejection Fraction) trial, a large multinational randomized trial with a target enrollment of 2,860 patients, is ongoing and will randomize patients with systolic heart failure to aspirin or warfarin (80).
Diabetes mellitus.
As is the case with other diseases that contribute to cardiovascular risk, many advocate the use of aspirin in patients with diabetes mellitus, even in the absence of strong evidence from major prospective clinical trials. One prime example is a subgroup analysis of patients with type 2 diabetes mellitus from the PPP (Primary Prevention Project) trial, one-half of whom were taking aspirin (81). This drug failed to reduce global cardiovascular events in diabetic patients, but did appear to confer a significant reduction in stroke events.
Despite the lack of prospective studies to support the use of low-dose aspirin in diabetic patients, this agent is considered a cornerstone of primary and secondary prevention of thrombotic cardiovascular, cerebral, and peripheral arterial events in both type 1 and type 2 diabetes mellitus (82–85). Much of the evidence for this argument stems directly from the Antiplatelet Trialists' Collaboration meta-analysis (10), which found a significant reduction in ischemic vascular events by use of aspirin in a subgroup of patients with diabetes mellitus.
There are only limited direct data on the prevalence of aspirin resistance in diabetes mellitus. Given the complex pathophysiology of diabetes mellitus and the frequent association with other disorders (e.g., hyperlipidemia, hyperglycemia, hypertension, endothelial dysfunction, chronic inflammation, accelerated atherogenesis, hypercoagulable state, micro- and macro-vasculopathy, and so on) all of which may significantly up-regulate COX-1–independent pathways of platelet activation and aggregation, it is considered that the prevalence of aspirin resistance is likely to be substantial (86,87). In a cohort of 488 patients with aspirin resistance in the HOPE (Heart Outcomes Prevention Evaluation) trial, 32.6% had diabetes mellitus (34). In a group of type 2 diabetic patients treated with aspirin 100 mg daily, the prevalence of aspirin resistance was estimated at 21.5% using the PFA-100 analyzer with collagen/epinephrine cartridges (88). However, the authors did not find any association between aspirin resistance and cardiovascular events after 1-year follow-up, nor any association between aspirin resistance and confounding factors (hyperlipidemia, hyperglycemia, hypertension, obesity, or smoking). This study was small, and further prospective long-term studies are required to assess the real clinical significance of aspirin resistance in diabetes.
Hypertension.
For secondary prevention, the benefit of antiplatelet therapy with aspirin in subjects with hypertension is well established and supported by strong trial data (89). For primary prevention, however, the evidence is less robust. In the large HOT (Hypertension Optimal Treatment) trial, the efficacy of aspirin in reducing major cardiovascular events (in particular, MI, not stroke) was evident, but aspirin increased the risk of major and minor nonfatal bleedings, and there was no major effect on mortality (14). Perhaps this may, in part, relate to aspirin resistance, as a significant proportion of patients (45% to 63.5%) with this phenomenon do, in fact, have hypertension (34,45). Nonetheless, little is known about aspirin response and its prognostic value in patients with arterial hypertension.
As appears to be the case with heart failure and with diabetes mellitus, a number of factors may contribute to altered platelet reactivity and lead to relatively high frequency of aspirin resistance among subjects with hypertension. As already discussed, this presumably occurs predominantly through activation of COX-1–independent mechanisms. In the case of hypertension, this is likely not only related to altered production of thromboxane A2, but also, given the pleiotropic function of aspirin, may be related to the activation of nitric oxide (NO) synthase and an increase in NO production by platelets (90). The increased NO may then counteract various prothrombotic and hypertensive factors, and, thereby, may be implicated in the clinical efficacy of aspirin.
In a recent study, Feher et al. (91) investigated the presence of hypertension and aspirin resistance among patients with cardiovascular and cerebrovascular disease who were taking aspirin 100 to 325 mg daily. They found a significantly higher prevalence of hypertension among aspirin-sensitive patients compared with that seen in aspirin-resistant patients (80% vs. 62%; p < 0.05). However, there was also a significantly higher rate of beta-blocker and ACE inhibitor usage among aspirin-sensitive patients; these drugs may exert an additive antiplatelet action when combined with aspirin. Oddly, the use of statins was shown to be an independent predictor of aspirin resistance.
Rheumatic diseases.
Autoimmune, inflammatory, and thrombotic reactions may be enhanced by various rheumatic diseases, and—in conjunction with classic cardiovascular risk factors—may accelerate the course of atherosclerosis, leading to premature manifestation(s) of cardiovascular disease (92–94). In this context, both the anti-inflammatory and the antiplatelet properties of aspirin may be crucial for primary and secondary prevention.
In a study of almost 9,000 cases of a first-time MI among patients registered on the British General Practice Research Database, the highest risk of MI was found in patients with rheumatoid arthritis or systemic lupus erythematosus (adjusted odds ratio 3.68; 95% CI 2.36 to 5.74) and in those following cessation of nonsteroidal anti-inflammatory drugs after long-term use (adjusted odds ratio 2.60, 95% CI 1.84 to 3.68) (95). In a post-mortem study of patients with rheumatoid arthritis, atherosclerosis was less prevalent among those subjects with a prolonged course of arthritis (more than 8 years) and regular aspirin use (96). An inverse relationship was found between the prevalence of symptomatic atherosclerosis and duration of aspirin intake.
Such findings should be considered carefully with evidence from a number of small studies suggesting that the efficacy of antiplatelet therapy with aspirin may be diminished by persistent inflammation (e.g., from rheumatic disease) and concurrent use of other nonsteroidal anti-inflammatory drugs, and may even be negated by the potential risk of major gastrointestinal hemorrhage (97,98). Large-scale, prospective studies investigating the relationship between low-dose aspirin usage, aspirin resistance, inflammation, and cardiovascular risk are awaited.
|
Therapeutic Opportunities for Aspirin Resistance
|
|---|
Aspirin resistance is a multifactorial phenomenon, and treatment should, therefore, be directed to a number of COX-1–dependent and –independent factors, some of which may be modifiable (e.g., patient compliance, aspirin dosage, drug–drug interactions, and increased platelet turnover). Adequate treatment of confounding clinical conditions such as smoking, hyperlipidemia, hyperglycemia, hypertension, heart failure, infection, and inflammation may further increase efficacy of antiplatelet treatment with aspirin.
In some patients, an increased dose of administered aspirin may prove useful to overcome resistance (e.g., acute coronary syndromes, infections, inflammation, and so on). This approach is unjustifiable and even unsafe in diabetes, chronic heart failure, and rheumatic heart disease. In addition, the available evidence does not consider aspirin doses higher than 81 mg as either effective or safe (56).
The most logical and promising approach, therefore, seems to be the addition of other antiplatelet or antithrombotic drugs to aspirin therapy rather than replacement of aspirin in clinical conditions where aspirin resistance is anticipated. In several studies, platelet sensitivity to ADP and levels of this agonist in patients with aspirin resistance were shown to be significantly increased (99,100). In addition, those patients with the least sensitivity to the effect of aspirin on the arachidonic acid pathway appeared to be highly sensitive to the P2Y12 platelet ADP receptor antagonist clopidogrel (101). Such data suggest the potential for dual antiplatelet therapy, and, consequently, this approach has been addressed by several large randomized trials (Table 4) (102–108).
Dual antiplatelet therapy with clopidogrel and aspirin demonstrates statistically significant additive benefit (in terms of primary end points and bleeding rate) over aspirin monotherapy in various clinical trials (COMMIT [ClOpidogrel and Metoprolol in Myocardial Infarction Trial], CURE [Clopidogrel in Unstable angina to prevent Recurrent Events], PCI-CURE [substudy of CURE], CREDO [Clopidogrel for the Reduction of Events During Observation]) (Table 4) (102–105).
In two large trials, the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial and the MATCH (Management of ATherothrombosis with Clopidogrel in High-risk patients) trial, with 15,603 and 7,599 high-risk cardiovascular and cerebrovascular patients, respectively, there was no difference in the primary end points between the dual and monotherapy arms of the trials. Importantly, of the broad range of high-risk atherothrombosis patients enrolled in the CHARISMA trial, a subgroup of 9,478 patients with prior MI, stroke, and symptomatic peripheral arterial disease did appear to benefit from dual antiplatelet therapy (109). In this subgroup analysis, the composite end point of cardiovascular death, MI, and stroke was lower in the clopidogrel plus aspirin arm compared with the placebo plus aspirin arm (7.3% vs. 8.8%; hazard ratio 0.83, 95% CI 0.72 to 0.96; p = 0.01). With regard to secondary end points, hospitalization rate over the mean follow-up period of 27.6 months was significantly lower in the clopidogrel plus aspirin arm (11.4% vs. 13.2%; hazard ratio 0.86, 95% CI 0.76 to 0.96; p = 0.008), and there was no difference in the rate of severe bleeding. This subgroup analysis of the CHARISMA trial stressed the importance of identifying selected patients who would benefit from dual antiplatelet therapy.
This notion is further supported by recent analysis of excess cardiovascular death rate in the CHARISMA trial of asymptomatic patients treated with dual antiplatelet therapy (110), and by results of 2 small studies, the PLUTO-CHF (PLavix Use for Treatment Of Congestive Heart Failure) (111) and prospective follow-up study of aspirin resistance by Pamukcu et al. (43). In the latter small studies, patients meeting criteria of laboratory aspirin resistance were randomly selected to receive clopidogrel plus aspirin therapy. In the PLUTO-CHF study, dual aspirin-clopidogrel therapy over 1 month resulted in significant changes in a number of platelet activation laboratory parameters in a small cohort (n = 25) of heart failure patients. Pamukcu et al. (43) reported 28 patients with coronary artery disease who were followed-up over a 6- to 12-month period, and those who received additional clopidogrel therapy over 12 months had less cardiovascular events than those who did not use or stopped clopidogrel at 6 months.
Although dual aspirin-clopidogrel therapy may seem to be the most beneficial therapeutic approach to aspirin resistance, a rapidly increasing number of publications recognize the existence of "clopidogrel resistance" (25,111–114) and even "dual aspirin-clopidogrel resistance" (115). These observations necessitate further search for new, more potent antiplatelet agents suitable for long-term cardiovascular prevention. Among these agents are thienopyridine compound, prasugrel (CS-747, LY 640315), which provides 10 times more potency, rapid and sustained antiplatelet effect, when compared with clopidogrel (111,116), and an oral reversible inhibitor of P2Y12 receptor AZD6140 (117).
Another approach to enhance antiplatelet effect of aspirin is an addition of dipyridamole. Combination therapy with aspirin and dipyridamole is used in the setting of secondary prevention after stroke. The evidence for this comes from the ESPS (European Stroke Prevention Study)-2 trial with 4 treatment arms (50 mg/day aspirin, 400 mg/day dipyridamole, dual therapy and placebo) (118). This trial showed 22% relative risk reduction of major vascular events in patients with dual aspirin-dipyridamole therapy compared with that seen with aspirin alone, but no significant effect on vascular death rate. Additionally, the ESPRIT (European/Australasian Stroke Prevention in Reversible Ischaemia Trial) study compared efficiency of aspirin (30 to 325 mg/day) with or without dipyridamole (400 mg/day) in patients with transient ischemic attack or minor stroke (119). The composite of vascular death, nonfatal stroke, nonfatal MI, and major bleeding was evaluated over a mean follow-up period of 3.5 years; superiority of clinical efficacy of combined therapy was demonstrated (absolute annual risk reduction 1.0%, 95% CI 0.1 to 1.8) (119). Nevertheless, it is noteworthy that meta-analysis by Antithrombotic Trialists' Collaboration showed no difference in efficacy between aspirin plus dipyridamole and aspirin alone in high vascular risk patients (10). These results were reiterated by a recent systematic review of 29 trials with more than 23,000 patients with arterial vascular disease (120). No evidence was found that dipyridamole alone or in combination with aspirin significantly reduced the risk of vascular death, although it was efficacious in secondary prevention of cerebrovascular ischemic events.
In patients undergoing percutaneous coronary angioplasty, significant improvement of clinical efficacy of aspirin alone or in combination with clopidogrel may be achieved by addition of cilostazol, a phosphodiesterase type 3 inhibitor with potent antiplatelet, vasodilative, antiproliferative, endothelial function, and lipid profile improving effects (121,122). In the CREST (Cilostazol for RESTenosis) trial, addition of cilostazol to aspirin and clopidogrel therapy reduced the rate of restenosis by 36% after successful bare-metal stenting (123). It proved to be efficient in patients with peripheral arterial disease as well (124).
Whether addition of new inhibitors of P2Y12 receptor, dipyridamole, or cilostazol to aspirin is an effective intervention for subjects with aspirin resistance remains to be elucidated in future studies.
|
Conclusions
|
|---|
Despite the emergence of "aspirin resistance" as a clinical phenomenon, aspirin still remains the most commonly prescribed drug for prevention of atherothrombotic events. This is due not only to its potent inhibition of the thromboxane A2 pathway, which is undoubtedly crucial for platelet activation and aggregation, but also because of a number of pleiotropic effects (suppression of acute phase reactants and subclinical inflammation, stimulation of NO synthesis, immunomodulatory effect on activated macrophages and lymphocytes, and so on) (125–127). Furthermore, aspirin has proved complementary to—and seems to potentiate—the effects of other antiplatelet agents (such as clopidogrel, dipyridamole, cilostazol) in the case of combined therapy. In addition, aspirin seems to be generally well tolerated by most patients, and relatively few have contraindications to this drug or develop major bleeding. Such characteristics mean that aspirin is likely to remain the cornerstone of antiplatelet therapy for long-term cardiovascular prevention.
As discussed in this review, numerous modifiable and nonmodifiable factors may interfere with aspirin therapy, preventing its targeted action on the thromboxane A2 pathway, thereby attenuating the effect of this drug on platelet activation and aggregation and limiting its role in cardiovascular prevention. The terms "biochemical or laboratory" and "clinical" aspirin resistance have been suggested to better characterize those patients who do not benefit from long-term aspirin use. Despite this, relatively few well-designed prospective studies have been conducted thus far, yielding some evidence that is suggestive of a possible link between the inefficient inhibition of thromboxane A2 pathway and adverse cardiovascular events over long-term follow-up. Unfortunately, these studies lack a standardized definition of aspirin resistance based on validated and widely available methods of platelet function assessment. As a matter of fact, studies comparing main laboratory tests for detection of aspirin resistance (optical and whole blood aggregometry, PFA-100, VerifyNow-Aspirin, level of urinary 11-dehydro-thromboxane B2) found poor agreement between these tests (128) and left unresolved the issue of utility of these tests for routine measurements of aspirin resistance.
The available evidence does not adequately address the issue of dynamic changes in platelet function and whether aspirin resistance persists over a period of time when multiple intrinsic and extrinsic factors may exert their effect on platelet function in multiple directions. To address this issue, design of future prospective studies should include baseline and follow-up measurements of platelet function in patients with accurately monitored compliance to long-term aspirin use.
Actually, future studies of aspirin resistance should also consider complex interactions between age, gender, and ethnicity, as it is becoming more obvious that these factors may have an impact on the extent of inhibition of COX-1 pathway by aspirin (129–131). Finally, the issue of aspirin resistance should be considered separately for those who may not benefit from aspirin due to COX-1–related and –nonrelated genetic factors (131). Until further studies are available to investigate aspirin resistance in more depth, a balanced approach is required when assessing patients for antiplatelet therapy. Certainly, comorbidities that may enhance aspirin resistance (e.g., diabetes mellitus, hypertension, heart failure, inflammatory disorders, and so on) should be actively sought, as this may aid the practicing clinician in deciding between monotherapy with aspirin or coprescription with other more potent antiplatelet drugs.
|
References
|
|---|
1. Levesque H, Lafont O. Aspirin throughout the ages: a historical review Rev Med Interne 2000;21(Suppl 1):8S-17S.[Web of Science][Medline]2. Vane JR. The fight against rheumatism: from willow bark to COX-1 sparing drugs J Physiol Pharmacol 2000;51:573-586.[Web of Science][Medline] 3. Marson P, Pasero G. The Italian contributions to the history of salicylates Reumatismo 2006;58:66-75.[Medline] 4. Vainio H, Morgan G. Aspirin for the second hundred years: new uses for an old drug Pharmacol Toxicol 1997;81:151-152.[Web of Science][Medline] 5. Vane JN. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs Nat New Biol 1971;231:232-235.[Web of Science][Medline] 6. Rao GH. Influence of anti-platelet drugs on platelet-vessel wall interactions Prostaglandins Leukot Med 1987;30:133-145.[CrossRef][Web of Science][Medline] 7. Koutts J. Aspirin and coronary heart disease. Clinical applications. Aust Fam Physician 1990;19:217221–3.[Medline] 8. Louden KA, Broughton Pipkin F, Heptinstall S, et al. Neonatal platelet reactivity and serum thromboxane B2 production in whole blood: the effect of maternal low dose aspirin Br J Obstet Gynaecol 1994;101:203-208.[Web of Science][Medline] 9. McAuliffe SJ, Moors JA, Jones HB. Comparative effects of anti-platelet agents as adjuncts to tissue plasminogen activator in a dog model of occlusive coronary thrombosis Br J Pharmacol 1994;112:272-276.[Web of Science][Medline] 10. 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.[Abstract/Free Full Text] 11. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men N Engl J Med 1997;336:973-979.[Abstract/Free Full Text] 12. Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors Br Med J (Clin Res Ed) 1988;296:313-316.[Medline] 13. Meade TW, Brennan PJ, Wilkes HC, Zuhrie SR. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk Lancet 1998;351:233-241.[CrossRef][Web of Science][Medline] 14. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT study group. Lancet 1998;351:1755-1762.[CrossRef][Web of Science][Medline] 15. de Gaetano G, Collaborative Group of the Primary Prevention Project Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice Lancet 2001;357:89-95.[CrossRef][Web of Science][Medline] 16. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women N Engl J Med 2005;352:1293-1304.[Abstract/Free Full Text] 17. Eidelman RS, Hebert PR, Weisman SM, Hennekens CH. An update on aspirin in the primary prevention of cardiovascular disease Arch Intern Med 2003;163:2006-2010.[Abstract/Free Full Text] 18. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials JAMA 2006;295:306-313.[Abstract/Free Full Text] 19. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2 Lancet 1988;2:349-360.[Medline] 20. Hennekens CH, Schror K, Weisman S, FitzGerald GA. Terms and conditions. Semantic complexity and aspirin resistance. Circulation 2004;110:1706-1708.[Free Full Text] 21. Mehta J, Mehta P, Burger C, Pepine CJ. Platelet aggregation studies in coronary artery disease. Part 4. Effect of aspirin. Atherosclerosis 1978;31:169-175.[Medline] 22. Sanderson S, Baglin T, Kinmonth AL. Narrative review: aspirin resistance and its clinical implications Ann Int Med 2005;142:370-380.[Abstract/Free Full Text] 23. Macchi L, Sorel N, Christiaens L. Aspirin resistance: definitions, mechanisms, prevalence, and clinical significance Curr Pharm Des 2006;12:251-258.[CrossRef][Web of Science][Medline] 24. Hankey GJ, Eikelboom JW. Aspirin resistance Lancet 2006;367:606-617.[CrossRef][Web of Science][Medline] 25. Wang TH, Bhatt DL, Topol EJ. Aspirin and clopidogrel resistance: an emerging clinical entity Eur Heart J 2006;27:647-654.[Abstract/Free Full Text] 26. Shantsila E, Watson T, Lip GYH. Aspirin resistance: what, why and when? Thrombosis Res 2007;119:551-554.[CrossRef][Web of Science][Medline] 27. Poulsen TS, Jørgensen B, Korsholm L, Licht PB, Haghfelt T, Mickley H. Prevalence of aspirin resistance in patients with an evolving acute myocardial infarction Thrombosis Res 2007;119:555-562.[CrossRef][Web of Science][Medline] 28. Gum PA, Kottke-Merchant K, Poggio ED, et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease Am J Cardiol 2001;88:230-235.[CrossRef][Web of Science][Medline] 29. Mammen EF, Comp PC, Gosselin R, et al. PFA-100 system: a new method for assessment of platelet dysfunction Semin Thromb Haemost 1998;24:195-202.[Web of Science][Medline] 30. Nicholson NS, Panzer-Knodle SG, Haas NF, et al. Assessment of platelet function assays Am Heart J 1998;135:S170-S178.[CrossRef][Web of Science][Medline] 31. Harrison P, Segal H, Blasbery K, Furtado C, Silver L, Rothwell PM. Screening for aspirin responsiveness after transient ischemic attack and stroke Stroke 2005;36:1001-1005.[Abstract/Free Full Text] 32. 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.[CrossRef][Web of Science][Medline] 33. Hart RG, Leonard AD, Talbert RL, et al. Aspirin dosage and thromboxane synthesis in patients with vascular disease Pharmacotherapy 2003;23:579-584.[CrossRef][Web of Science][Medline] 34. Eikelboom JW, Hirsh J, Weitz JI, Johnson M, Yi Q, Yusuf S. Aspirin resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events Circulation 2002;105:1650-1655.[Abstract/Free Full Text] 35. 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.[Abstract/Free Full Text] 36. Choudhury A, Chung I, Blann AD, Lip GY. Platelet surface CD62P and CD63, mean platelet volume, and soluble/platelet P-selectin as indexes of platelet function in atrial fibrillation: a comparison of "healthy control subjects" and "disease control subjects" in sinus rhythm J Am Coll Cardiol 2007;49:1957-1964.[Abstract/Free Full Text] 37. Choudhury A, Chung I, Blann AD, Lip GY. Elevated platelet microparticle levels in nonvalvular atrial fibrillation: relationship to P-selectin and antithrombotic therapy Chest 2007;131:809-815.[CrossRef][Web of Science][Medline] 38. Nadar S, Blann AD, Lip GY. Effects of aspirin on intra-platelet vascular endothelial growth factor, angiopoietin-1, and p-selectin levels in hypertensive patients Am J Hypertens 2006;19:970-977.[CrossRef][Web of Science][Medline] 39. Hovens MM, Snoep JD, Eikenboom JC, van der Bom JG, Mertens BJ, Huisman MV. Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review Am Heart J 2007;153:175-181.[CrossRef][Web of Science][Medline] 40. 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.[CrossRef][Web of Science][Medline] 41. Gum PA, Kottke-Merchant 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.[Abstract/Free Full Text] 42. 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.[Web of Science][Medline] 43. 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 Coagul Fibrinolysis 2007;18:187-192.[Web of Science][Medline] 44. Martin CP, Talbert RL. Aspirin resistance: an evaluation of current evidence and measurement methods Pharmacotherapy 2005;25:942-953.[CrossRef][Web of Science][Medline] 45. Szczeklik A, Undas A, Sanak M, Frolow M, Wegrzyn W. Relationship between bleeding time, aspirin and the PlA1/A2 polymorphism of platelet glycoprotein IIIa Br J Haematol 2000;110:965-967.[CrossRef][Web of Science][Medline] 46. Papp E, Havasi V, Bene J, et al. Glycoprotein IIIA gene (PlA) polymorphism and aspirin resistance: is there any correlation? Ann Pharmacother 2005;39:1013-1018.[Abstract/Free Full Text] 47. Dropinski J, Musial J, Sanak M, Wegrzyn W, Nizankowski R, Szczeklik A. Antithrombotic effects of aspirin based on PLA1/A2 glycoprotein IIIa polymorphism in patients with coronary artery disease Thromb Res 2007;119:301-303.[CrossRef][Web of Science][Medline] 48. Gonzalez-Conejero R, Rivera J, Corral J, Acuna C, Guerrero JA, Vicente V. Biological assessment of aspirin efficacy on healthy individuals: heterogeneous response or aspirin failure? Stroke 2005;36:276-280.[Abstract/Free Full Text] 49. 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.[CrossRef][Web of Science][Medline] 50. Cambria-Kiely JA, Gandhi PJ. Aspirin resistance and genetic polymorphisms J Thromb Thrombolysis 2002;14:51-58.[CrossRef][Web of Science][Medline] 51. FitzGerrald GA. Parsing an enigma: the pharmacodynamics of aspirin resistance Lancet 2003;361:542-544.[CrossRef][Web of Science][Medline] 52. Schwartz KA. Aspirin resistance: a review of diagnostic methodology, mechanisms, and clinical utility Adv Clin Chem 2006;42:81-110.[Web of Science][Medline] 53. 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.[Abstract/Free Full Text] 54. Rottlaender D, Scherner M, Schneider T, Erdmann E. Polypharmacy, compliance and non-prescription medication in patients with cardiovascular disease in Germany Dtsch Med Wochenschr 2007;132:139-144.[CrossRef][Medline] 55. 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.[CrossRef][Web of Science][Medline] 56. Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin dose for the prevention of cardiovascular disease. A systematic review. JAMA 2007;297:2018-2024.[Abstract/Free Full Text] 57. 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.[Abstract/Free Full Text] 58. Zimmermann N, Kurt M, Wenk A, Winter J, Gams E, Hohlfeld T. Is cardiopulmonary bypass a reason for aspirin resistance after coronary artery bypass grafting? Eur J Cardiothorac Surg 2005;27:606-610.[Abstract/Free Full Text] 59. Guthikonda S, Lev EI, Patel R, et al. Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin J Thromb Haemost 2007;5:490-496.[CrossRef][Web of Science][Medline] 60. Modica A, Karlsson F, Mooe T. Platelet aggregation and aspirin non-responsiveness increase when an acute coronary syndrome is complicated by an infection J Thromb Haemost 2007;5:507-511.[CrossRef][Web of Science][Medline] 61. Ferroni P, Basili S, Falco A, Davi G. Platelet activation in type 2 diabetes mellitus J Thromb Haemost 2004;2:1282-1291.[CrossRef][Web of Science][Medline] 62. Anfossi G, Trovati M. Pathophysiology of platelet resistance to anti-aggregating agents in insulin resistance and type 2 diabetes: implications for anti-aggregating therapy Cardiovasc Hematol Agents Med Chem 2006;4:111-128.[Medline] 63. Watala C. Blood platelet reactivity and its pharmacological modulation in (people with) diabetes mellitus Curr Pharm Des 2005;11:2331-2365.[CrossRef][Web of Science][Medline] 64. Davi G, Alessandrini P, Mezzetti A, et al. In vivo formation of 8-Epi-prostaglandin F2 alpha is increased in hypercholesterolemia Arterioscler Thromb Vasc Biol 1997;17:3230-3235.[Abstract/Free Full Text] 65. Reilly M, Delanty N, Lawson JA, FitzGerald GA. Modulation of oxidant stress in vivo in chronic cigarette smokers Circulation 1996;94:19-25.[Abstract/Free Full Text] 66. Polidori MC, Pratico D, Savino K, Rokach J, Stahl W, Mecocci P. Increased F2 isoprostane plasma levels in patients with congestive heart failure are correlated with antioxidant status and disease severity J Card Fail 2004;10:334-338.[CrossRef][Web of Science][Medline] 67. White M, Ducharme A, Ibrahim R, et al. Increased systemic inflammation and oxidative stress in patients with worsening congestive heart failure: improvement after short-term inotropic support Clin Sci (Lond) 2006;110:483-489.[Medline] 68. Chung I, Lip GY. Platelets and heart failure Eur Heart J 2006;27:2623-2631.[Abstract/Free Full Text] 69. 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.[CrossRef][Web of Science][Medline] 70. Frelinger AL, Furman MI, Linden, MD, et al. Residual arachidonic acid-induced platelet activation via an adenosine diphosphate-dependent but cyclooxygenase-1- and cyclooxygenase-2-independent pathway: a 700-patient study of aspirin resistance Circulation 2006;113:2888-2896.[Abstract/Free Full Text] 71. Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection J Thromb Haemost 2007(Suppl 1):230-237. 72. Dotsenko O, Kakkar VV. Antithrombotic therapy in patients with chronic heart failure: rationale, clinical evidence and practical implications J Thromb Haemost 2007;5:224-231.[CrossRef][Web of Science][Medline] 73. Lip GY, Gibbs CR. Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm Cochrane Database Syst Rev 2001;4CD003333. 74. Masoudi FA, Wolfe P, Havranek EP, Rathore SS, Foody JM, Krumholz HM. Aspirin use in older patients with heart failure and coronary artery disease: national prescription patterns and relationship with outcomes J Am Coll Cardiol 2005;46:955-962.[Abstract/Free Full Text] 75. McAlister FA, Ghali WA, Gong Y, Fang J, Armstrong PW, Tu JV. Aspirin use and outcomes in a community-based cohort of 7352 patients discharged after first hospitalization for heart failure Circulation 2006;113:2572-2578.[Abstract/Free Full Text] 76. Cleland JG, Findlay I, Jafri S, et al. The Warfarin/Aspirin Study in Heart Failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure Am Heart J 2004;148:157-164.[CrossRef][Web of Science][Medline] 77. Massie BM, Krol WF, Ammon SE, et al. The Warfarin and Antiplatelet Therapy in Heart Failure trial (WATCH): rationale, design, and baseline patient characteristics J Card Fail 2004;10:101-112.[CrossRef][Web of Science][Medline] 78. Cokkinos DV, Toutouzas PK. Antithrombotic therapy in heart failure: a randomized comparison of warfarin vs. aspirin (HELAS) Eur J Heart Fail 1999;1:419-423.[CrossRef][Web of Science][Medline] 79. Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK, HELAS Investigators Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study Eur J Heart Fail 2006;8:428-432.[CrossRef][Web of Science][Medline] 80. WARCEF Investigators Warfarin versus aspirin in patients with reduced cardiac ejection fraction (WARCEF): rationale, objectives, and design J Card Fail 2006;12:39-46.[CrossRef][Web of Science][Medline] 81. Sacco M, Pellegrini F, Roncaglioni MC, Avanzini F, Tognoni G, Nicolucci A. Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial Diabetes Care 2003;26:3264-3272.[Abstract/Free Full Text] 82. Colwell JA. Antiplatelet agents for the prevention of cardiovascular disease in diabetes mellitus Am J Cardiovasc Drugs 2004;4:87-106.[CrossRef][Medline] 83. Berry C, Tardif JC, Bourassa MG. Coronary heart disease in patients with diabetes: part I: recent advances in prevention and noninvasive management J Am Coll Cardiol 2007;49:631-642.[Abstract/Free Full Text] 84. Cull CA, Neil HA, Holman RR. Changing aspirin use in patients with type 2 diabetes in the UKPDS Diabet Med 2004;21:1368-1371.[CrossRef][Web of Science][Medline] 85. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular disease in people with diabetes mellitus. A scientific statement from the American Heart Association and the American Diabetes Association. Circulation 2007;115:114-126.[Abstract/Free Full Text] 86. Coccheri S. Approaches to prevention of cardiovascular complications and events in diabetes mellitus Drugs 2007;67:997-1026.[CrossRef][Web of Science][Medline] 87. Evangelista V, Totani L, Rotondo S, et al. Prevention of cardiovascular disease in type-2 diabetes: how to improve the clinical efficacy of aspirin Thromb Haemost 2005;93:8-16.[Web of Science][Medline] 88. Fateh-Moghadam S, Plöckinger U, Cabeza N, et al. Prevalence of aspirin resistance in patients with type 2 diabetes Acta Diabetol 2005;42:99-103.[CrossRef][Web of Science][Medline] 89. Lip GY, Felmeden DC. Antiplatelet agents and anticoagulants for hypertension Cochrane Database Syst Rev 2004;3CD003186. 90. Madajka M, Korda M, White J, Malinski T. Effect of aspirin on constitutive nitric oxide synthase and the bioavailability of NO Thromb Res 2003;110:317-321.[CrossRef][Web of Science][Medline] 91. 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.[CrossRef][Web of Science][Medline] 92. Roman MJ, Shanker BA, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus N Engl J Med 2003;349:2399-2406.[Abstract/Free Full Text] 93. Abusamieh M, Ash J. Atherosclerosis and systemic lupus erythematosus Cardiol Rev 2004;12:267-275.[CrossRef][Medline] 94. Maradit-Kremers H, Crowson CS, Nicola PJ, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study Arthritis Rheum 2005;52:402-411.[CrossRef][Web of Science][Medline] 95. Fischer LM, Schlienger RG, Matter CM, Jick H, Meier CR. Discontinuation of nonsteroidal anti-inflammatory drug therapy and risk of acute myocardial infarction Arch Intern Med 2004;164:2472-2476.[Abstract/Free Full Text] 96. Sloop GD. Decreased prevalence of symptomatic atherosclerosis in arthritis patients on long-term aspirin therapy Angiology 1998;49:827-832.[Web of Science][Medline] 97. Kurth T, Hennekens CH, Buring JE, Gaziano JM. Aspirin, NSAIDs, and COX-2 inhibitors in cardiovascular disease: possible interactions and implications for treatment of rheumatoid arthritis Curr Rheumatol Rep 2004;6:351-356.[CrossRef][Medline] 98. Corman SL, Fedutes BA, Ansani NT. Impact of nonsteroidal antiinflammatory drugs on the cardioprotective effects of aspirin Ann Pharmacother 2005;39:1073-1079.[Abstract/Free Full Text] 99. 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.[CrossRef][Web of Science][Medline] 100. Borna C, Lazarowski E, van Heusden C, Öhlin H, Erlinge D. Resistance to aspirin is increased by ST-elevation myocardial infarction and correlates with adenosine diphosphate levels Thromb J 2005;3:10.[CrossRef][Medline] 101. 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;3:2649-2655.[CrossRef][Web of Science][Medline] 102. Chen ZM, Jiang LX, Chen YP, et al. COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial Lancet 2005;366:1607-1621.[CrossRef][Web of Science][Medline] 103. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation N Engl J Med 2001;345:494-502.[Abstract/Free Full Text] 104. Mehta SR, Yusuf S, Peters RJ, et al. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators 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.[CrossRef][Web of Science][Medline] 105. Steinhubl SR, Berger PB, Mann JT, et al. CREDO Investigators Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-2420.[Abstract/Free Full Text] 106. Markus HS, Droste DW, Kaps M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using Doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial Circulation 2005;111:2233-2240.[Abstract/Free Full Text] 107. Bhatt DL, Fox KA, Hacke W, et al. CHARISMA Investigators Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events N Engl J Med 2006;354:1706-1717.[Abstract/Free Full Text] 108. Diener HC, Bogousslavsky J, Brass LM, et al. MATCH Investigators Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial Lancet 2004;364:331-337.[CrossRef][Web of Science][Medline] 109. Bhatt DL, Flather, MD, Hacke W, et al. CHARISMA Investigators Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial J Am Coll Cardiol 2007;49:1982-1988.[Abstract/Free Full Text] 110. Wang TH, Bhatt DL, Fox KA, et al. An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial Eur Heart J 2007;28:2200-2207.[Abstract/Free Full Text] 111. Serebruany VL, Malinin AI, Jerome SD, et al. Effects of clopidogrel and aspirin combination versus aspirin alone on platelet aggregation and major receptor expression in patients with heart failure: the Plavix Use for Treatment Of Congestive Heart Failure (PLUTO-CHF) trial Platelets 2004;15:117-125.[CrossRef][Web of Science][Medline] 112. Michos ED, Ardenali R, Blumenthal RS, Lange RA, Ardenali H. Aspirin and clopidogrel resistance Mayo Clin Proc 2006;81:518-526.[Abstract/Free Full Text] 113. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Jukema JW, Huisman MV. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis Am Heart J 2007;154:221-231.[CrossRef][Web of Science][Medline] 114. Parikh SA, Beckman JA. Contemporary use of clopidogrel in patients with coronary artery disease Curr Cardiol Rep 2007;9:257-263.[Medline] 115. 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.[Abstract/Free Full Text] 116. Jakubowski JA, Matsushima N, Asai F, et al. A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans Br J Clin Pharmacol 2007;63:421-430.[CrossRef][Web of Science][Medline] 117. Steinhubl S, Roe MT. Optimizing platelet P2Y12 inhibition for patients undergoing PCI Cardiovasc Drug Rev 2007;25:188-203.[CrossRef][Web of Science][Medline] 118. The ESPS-2 Group European Stroke Prevention Study 2: efficacy and safety data J Neurol Sci 1997;151(Suppl):S1-S77.[Web of Science][Medline] 119. Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A, ESPRIT Study Group Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial Lancet 2006;367:1665-1673.[CrossRef][Web of Science][Medline] 120. De Schryver E, Algra A, van Gijn J. Dipyridamole for preventing stroke and other vascular events in patients with vascular disease Cochrane Database Syst Rev 2007;3CD001820. 121. Rao AK, Vaidyula VR, Bagga S, et al. Effect of antiplatelet agents clopidogrel, aspirin, and cilostazol on circulating tissue factor procoagulant activity in patients with peripheral arterial disease Thromb Haemost 2006;96:738-743.[Web of Science][Medline] 122. Dalainas I. Cilostazol in the management of vascular disease Int Angiol 2007;26:1-7.[Web of Science][Medline] 123. Douglas Jr. JS, Holmes Jr. DR, Kereiakes DJ, et al. Cilostazol for Restenosis Trial (CREST) Investigators Coronary stent restenosis in patients treated with cilostazol Circulation 2005;112:2826-2832.[Abstract/Free Full Text] 124. Robless P, Mikhailidis DP, Stansby GP. Cilostazol for peripheral arterial disease Cochrane Database Syst Rev 2007;1CD003748. 125. Krayenbuehl PA, Wiesli P, Schmid M, et al. TNF-alpha-308G>A polymorphism modulates cytokine serum concentrations and macrovascular complications in diabetic patients on aspirin Exp Clin Endocrinol Diabetes 2007;115:322-326.[CrossRef][Web of Science][Medline] 126. Chakraborty K, Khan GA, Banerjee P, Ray U, Sinha AK. Inhibition of human blood platelet aggregation and the stimulation of nitric oxide synthesis by aspirin Platelets 2003;14:421-427.[Medline] 127. Cho JY. Immunomodulatory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) at the clinically available doses Arch Pharm Res 2007;30:64-74.[Web of Science][Medline] 128. Lordkipanidzé M, Pharand C, Schampaert E, Turgeon J, Palisaitis DA, Diodati JG. 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.[Abstract/Free Full Text] 129. Faraday N, Yanek LR, Mathias R, et al. Heritability of platelet responsiveness to aspirin in activation pathways directly and indirectly related to cyclooxygenase-1 Circulation 2007;115:2490-2496.[Abstract/Free Full Text] 130. Becker DM, Segal J, Vaidya D, et al. Sex differences in platelet reactivity and response to low-dose aspirin therapy JAMA 2006;295:1420-1427.[Abstract/Free Full Text] 131. Li Q, Chen BL, Ozdemir V, et al. Frequency of genetic polymorphisms of COX1, GPIIIa and P2Y1 in a Chinese population and association with attenuated response to aspirin Pharmacogenomics 2007;8:577-586.[CrossRef][Web of Science][Medline]
This article has been cited by other articles:
|
|
|
|
 
E. I. Lev, A. Solodky, N. Harel, A. Mager, D. Brosh, A. Assali, M. Roller, A. Battler, N. S. Kleiman, and R. Kornowski
Treatment of Aspirin-Resistant Patients With Omega-3 Fatty Acids Versus Aspirin Dose Escalation
J. Am. Coll. Cardiol.,
January 12, 2010;
55(2):
114 - 121.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Paniccia, E. Antonucci, N. Maggini, E. Romano, A. M. Gori, R. Marcucci, D. Prisco, and R. Abbate
Assessment of Platelet Function on Whole Blood by Multiple Electrode Aggregometry in High-Risk Patients With Coronary Artery Disease Receiving Antiplatelet Therapy
Am J Clin Pathol,
June 1, 2009;
131(6):
834 - 842.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Rivera, M. L. Lozano, L. Navarro-Nunez, and V. Vicente
Platelet receptors and signaling in the dynamics of thrombus formation
Haematologica,
May 1, 2009;
94(5):
700 - 711.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. I. Lev
Aspirin resistance transient laboratory finding or important clinical entity?
J. Am. Coll. Cardiol.,
February 24, 2009;
53(8):
678 - 680.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. A. Kottke
The Ultimate Solution to the Problem of Aspirin Resistance
J. Am. Coll. Cardiol.,
October 7, 2008;
52(15):
1276 - 1276.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Y. Gasparyan and G. Y.H. Lip
Reply
J. Am. Coll. Cardiol.,
October 7, 2008;
52(15):
1277 - 1277.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Kapoor
Enteric Coating Is a Possible Cause of Aspirin Resistance
J. Am. Coll. Cardiol.,
October 7, 2008;
52(15):
1276 - 1277.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. A. Ofosu, L. Dewar, S. J. Craven, Y. Song, A. Cedrone, J. Freedman, and J. W. Fenton II
Coordinate Activation of Human Platelet Protease-activated Receptor-1 and -4 in Response to Subnanomolar {alpha}-Thrombin
J. Biol. Chem.,
October 3, 2008;
283(40):
26886 - 26893.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Trenk and F.-J. Neumann
Aspirin Resistance: An Underestimated Risk in Patients With Drug-Eluting Stents?
J. Am. Coll. Cardiol.,
August 26, 2008;
52(9):
740 - 742.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. W. Kamphuisen
Thrombogenicity in patients with percutaneous coronary artery intervention and dual antiplatelet treatment
Eur. Heart J.,
July 2, 2008;
29(14):
1699 - 1700.
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Search Criteria