Abstract
Aim:Aspirin resistance is recognized in different population. However, the prevalence and clinical events of aspirin resistance in elderly male patients with cardiovascular disease (CVD) have not been reported. Methods: We enrolled 304 elderly male patients with CVD receiving daily aspirin therapy (≥ 75 mg) more than 1 month. Platelet aggregation was measured by light transmission aggregometry (LTA) and thrombelastography platelet mapping assay (TEG). The median follow-up time was 1.8 years. The primary outcome was the composite of death, myocardial infarction, unstable angina, stroke and transient ischemic attack. Results: By LTA, 25 (8.2%) of elderly patients were aspirin resistant and 106 (34.9%) patients were semiresponders. According to TEG, 62 patients (20.4%) were found to be resistant to aspirin therapy. Of the 62 patients with aspirin resistance by TEG, 21 patients were aspirin resistant by LTA. Twenty-two of the 106 semiresponders by LTA were aspirin resistant by TEG. Patients with aspirin resistance or aspirin semiresponders were at increased risk of the composite outcome compared with aspirin-sensitive patients by LTA (18.3% vs 9.8%, Hazard ratio (HR) = 1.864, 95% confidence interval (CI): 1.046–3.324 p = 0.039). However, aspirin resistance was not associated with an increased risk of clinical vascular events compared to aspirin-sensitive patients by TEG (17.7% vs 10.9%, p = 0.452). In addition, Cox proportional hazard regression modeling demonstrated that aspirin resistance or semiresponders (HR = 3.050, 95% CI: 1.464–6.354, p = 0.003) and diabetes (HR = 2.055, 95% CI: 1.060–3.981, p = 0.033) were associated with major adverse long-term outcomes.Conclusions: Aspirin resistance or semiresponders, defined by LTA, are associated with an increased risk of adverse clinical events in elderly male patients with CVD.
Introduction
Cardiovascular disease (CVD) is the major cause of death in elderly patients worldwide, which is increased in the prevalence and mortality with advancing age [Citation1,Citation2]. The incidence of CVD in men is high compared with women among adults aged 45 years [Citation3]. Aspirin has been used in the primary and secondary prevention of thromboembolic vascular events. A large meta-analysis from Antithrombotic Trialists’ Collaboration (287 randomized trials of antiplatelet therapy) reported that antiplatelet treatment (aspirin in most studies) reduced the risk of ischaemic events of nonfatal myocardial infarction (MI), nonfatal stroke and vascular death by 32% [Citation4]. However, some studies have suggested that the antiplatelet effect of aspirin may not be uniform in all patients [Citation5,Citation6]. The lack of the expected antiplatelet effect of aspirin is defined as aspirin resistance or aspirin insensitivity or unresponsiveness to aspirin.
The prevalence of aspirin resistance is 5.5–60% for subjects [Citation7], because there are a number of methods for platelet function testing such as light transmission aggregometry (LTA), impedance aggregometry, thrombelastography platelet mapping assay (TEG), VerifyNow, platelet function analyzer-100 (PFA-100), phosphorylation of vasodilator-stimulated phosphoprotein, serum thromboxane B2 (TXB2), urinary 11-dehydro TXB2, platelet surface P-selectin, platelet surface-activated GP IIb/IIIa levels, which measures different aspects of platelet function, and individual methods may yield variable results [Citation8]. Unfortunately, a meta-analysis demonstrated that a cardiovascular event occurred in 39% of aspirin-resistant patients compared with 16% of aspirin-sensitive patients (odds ratio (OR) = 3.85, 95% confidence interval (CI) 3.08–4.80; p < 0.001), which enrolled 2930 patients with CVD [Citation9]. There are many potential mechanisms for aspirin resistance. Aspirin resistance is more common in patients with diabetes, post-myocardial infarction, smoking and hyperlipidemia, suggesting that some factors such as inflammation could play an important role in determining the platelet response to aspirin due to increased platelet activity and thromboxane production [Citation10,Citation11]. Aspirin resistance has been linked to polymorphisms in the platelet COX-1andCOX-2genes, the platelet glycoprotein receptor genes and the UDP-glucuronosyl-transferase gene [Citation11,Citation12]. In addition, noncompliance, inadequate dose or concomitant treatment with interacting medications, can be considered to be a major cause of aspirin resistance [Citation11–15]. Although aspirin resistance is recognized in different population, the prevalence and clinical events of aspirin resistance in elderly male patients with CVD have not been reported. We therefore undertook this study to investigate these associations among elderly male patients with CVD.
Subjects and methods
Ethical approval of the study protocol
This study complied with the Declaration of Helsinki. It was approved by the Scientific and Ethics Review Board of the First Geriatric Cardiology Division, Chinese PLA General Hospital (Beijing, P. R. China). All patients provided written informed consent to be included in the study.
Participants
Initially, we enrolled 337 patients from April 2008 to June 2010. Patients were recruited from the Wangshoulu area of Beijing, China. Patients were aged ≥ 65 years and were being treated for coronary heart disease, hypertension, peripheral arterial disease, stroke; all patients were on regular treatment with aspirin (75–100 mg daily more than 1 month). Equally, we recorded the conditions of patients in detail, including age, smoking history, history of diabetes and medications and body mass index (BMI = body weight (kg)/height (m2)). The exclusion criteria were hypersensitivity to aspirin; the use of clopidogrel, ticlopidine, dipyridamole or other non-steroidal anti-inflammatory drugs, heparin or low-molecular-weight heparin; a major surgical procedure within 1 week before the enrolment of study; family or personal history of bleeding disorders; platelet count <150 × 103/µL or >450 × 103/µL; hemoglobin <8 g/dL; history of myeloproliferative disorders; or a history of drug-induced thrombocytopenia. After enrollment, patients with poor compliance (n = 15), inadequate dose (≤ 75 mg) (n = 10), taking other antiplatelet medications (n = 8) were excluded during the follow-up. Thus, 304 patients were eventually included in the present study.
Blood sampling
Blood samples were obtained 2–12 h after the administration of the last dose of aspirin. The first 2 mL of blood drawn by venipuncture was discarded. Four tubes of whole blood, anticoagulated with 3.2% sodium citrate and lithium heparin were used for LTA and TEG. One tube that contained lithium heparin was also used for TEG. In addition, one tube of blood anticoagulated with a clavicular tilt angle difference (CTAD; a mixture of citrate, theophylline, adenosine and dipyridamole) was used for measurements of CD62P (P-selectin) and PAC-1 (activated GP IIb/IIIa receptors). Moreover, four conventional tubes were collected for: high-sensitivity C-reactive protein (CRP), type-B natriuretic peptide and protein C; the percentage activity of antithrombin III; routine measurements of blood components and blood lipids; and other biochemistry measurements. All assays were processed within 2 h of blood sampling.
Light transmission aggregometry
Blood samples were centrifuged at 800 rpm for 5 min to obtain native platelet-rich plasma and further centrifuged at 4000 rpmfor 8 min to obtain platelet-poor plasma. The platelet count was assessed using a standard cell counter. Aggregation was performed using arachidonic acid (AA; 0.5 mM) and adenosine diphosphate (ADP; 10 µM) with a ChronoLog Aggregometer (Chronolog, Havertown, PA).
TEG platelet-mapping assay
The TEG Platelet Mapping Assay (Haemoscope, Niles, IL) relies on the measurement of platelet function through the clot strength. AA (1 mmol/L) was added to activator F to measure the degree of thromboxane A2 (TXA2)-induced platelet aggregation. This methodology is described elsewhere [Citation16].
Other laboratory analyses
The hemoglobin assay and platelet counts were performed on a SYSMEX-XE2100 analyzer (SYSMEX, Kobe, Japan). Serum creatinine, blood lipid, homocysteine, high-sensitivity CRP, type-B natriuretic peptide and uric acid, as well as other basic biochemical blood tests, were measured by standard chemical and enzymatic commercial methods in a cobas 6000 analyzer series (Roche Diagnostic). The percentage activity of antithrombin III and protein C was tested by a STA-R Evolutioncoagulation analyzer (Stago, Paris, France).
Definition of aspirin resistance
The definitions of aspirin resistance were ≥ 20% AA- and ≥ 70% ADP-induced aggregation according to LTA. Aspirin semiresponders were defined as meeting one (but not both) of the criteria described above [Citation17,Citation18]. By TEG, aspirin resistance was defined as ≥ 50% aggregation induced by AA [Citation16]. The definition of aspirin resistance is generally accepted that insufficient suppression of platelet aggregation or function is evaluated by platelet function assay. Nevertheless, the most important problem with the term aspirin resistance is the lack of consensus on biological definitions.
Study end points
The primary end point was the composite of adverse clinical events, including death, MI, stroke, transient ischemic attack (TIA) and unstable angina. Death was defined as the death from vascular and nonvascular causes. MI was defined by the European Society of Cardiology/American College of Cardiology criteria [Citation19]. Stroke was defined as an acute neurologic vascular event lasting more than 24 h. TIA was defined as an acute neurologic vascular event lasting less than 24 h. Unstable angina was defined according to the American College of Cardiology Foundation/ American Heart Association criteria [Citation20].
Follow-up
The follow-up was completed in all patients by telephone interviews and review of medical records. Personnel performing data collection were blind to the platelet response to aspirin. The median follow-up time was 1.8 years. An expected clinical rate both in the aspirin resistance and aspirin sensitivity is 24 and 10%, respectively according to the previous study [Citation5].
Statistical analyses
Continuous variables are mean ± standard deviation. For continuous variables, analyses of univariate tests or Kruskal–Wallis tests were used to compare the three groups as measured by platelet aggregation. Comparisons between two groups were performed by using the Student’s t-test or Mann–Whitney U two-sample tests. Categorical data and proportions were compared using the χ2 test. p < 0.05 was considered significant. Cumulative survival curves for both aspirin-resistant and aspirin-sensitive groups were constructed by the Kaplan–Meier method. COX proportional hazards regression model was performed to describe the risk factors for clinical events (SPSS, Windows, version 14.0, Chicago, IL).
Results
Patient characteristics
Demographics, comparing aspirin-resistant patients, aspirin semiresponders and aspirin-sensitive patients evaluated by LTA and TEG are shown in and . According to LTA, serum high-density lipoprotein (HDL)cholesterol levels were higher in aspirin-sensitive patients (p = 0.035). The patients of aspirin resistance + aspirin semi-responders were less likely to take nitrates as the therapy than aspirin-sensitive patients (p = 0.037). Aspirin-sensitive patients had lower levels of CD62P and higher levels of HDL cholesterol than the combined group (p = 0.022 and p = 0.029 respectively).
Table I. Patient demographics by light transmission aggregometry.
Table II. Patient demographics by thrombelastography platelet mapping assay.
By TEG, aspirin-resistant patients had higher levels of fasting serum glucose compared with aspirin-sensitive patients (p = 0.007). Aspirin-sensitive patients were more likely to take angiotensin-converting enzyme inhibitors or angiotensin receptor blockers as the therapy than aspirin-resistant patients (p = 0.015).
Testing of platelet aggregation
By LTA, 25 (8.2%) of elderly patients were aspirin resistant and 106 (34.9%) patients were semiresponders. According to TEG, 62 patients (20.4%) were aspirin resistant. Of the 62 patients with aspirin resistance by TEG, 21 patients were aspirin resistant by LTA. Twenty-two of 106 semiresponders by LTA were aspirin resistant by TEG. The κ statistic between these two methods was 0.440 (95% CI: 0.3427–0.5373). There were no significant differences with regard to the prevalence of aspirin resistance among age groups ().
Table III. Age-specific prevalence of aspirin resistance or semiresponders in patients with cardiovascular disease.
Follow-up, clinical vascular events
During the follow-up, patients with aspirin resistance or aspirin semiresponders were at increased risk of the composite outcome compared with aspirin-sensitive patients by LTA (18.3% vs 9.8%, Hazard ratio (HR) = 1.864, 95% CI: 1.046–3.324 p = 0.039). However, aspirin resistance was not associated with an increased risk of clinical vascular events compared to aspirin-sensitive patients by TEG (17.7% vs 10.9%, p = 0.452) (). The Kaplan–Meier curves of the probability of survival without clinical events reached a significant difference between the two groups defined by LTA (p = 0.0001) ().
Table IV. Occurrence of composite end point in the aspirin-resistant patients or semiresponders and aspirin-sensitive patients.
Figure 1. Kaplan–Meier curves of probability of freedom from composite end point according to response to aspirin therapy. Composite end point included myocardial infarction, stroke, transient ischemic attack and unstable angina. Patients were defined as aspirin resistant by different methods.
Cox proportional hazard regression analysis
Cox proportional hazard regression modeling demonstrated that aspirin resistance or semiresponders (HR = 3.050, 95% CI: 1.464–6.354, p = 0.003), and diabetes (HR = 2.055, 95% CI: 1.060–3.981, p = 0.033) were associated with major adverse long-term outcomes ().
Table V. Hazard ratios of the composite end point by Cox proportional hazards regression.
Discussion
Among patients with CVD, the present study showed, for the first time, that the prevalence of aspirin resistance by LTA was 8.2% in elderly male patients. A low prevalence (0–2%) of aspirin resistance was observed in 120 patients with stable coronary artery disease (CAD) as determined by AA-induced LTA [Citation21]. Several studies demonstrated that prevalence of aspirin resistance was from 2.8 to 11.1% by using LTAAAand LTAADP in patients with cardiovascular patients [Citation17,Citation18,Citation22]. However, 62 patients (20.4%) were aspirin resistant according to TEG in the present study. The prevalence of aspirin resistance was 9% defined by AA-induced TEG with ≥ 50% aggregationin 120 patients with coronary artery [Citation23]. The rate of aspirin resistance was 33% detected by AA-induced TEG with a reactivity of maximum amplitude (MA) >20% in 81 patients with CVD [Citation24]. The frequency of aspirin resistance in our study was similar with those found in previous studies.
The present study showed that diabetes was an independent risk factor for clinical events. Chen et al. [Citation6] also demonstrated that diabetes mellitus was an independent predictor of unfavorable clinical outcomes on long-term follow-up in 468 stable CAD patients. In addition, Arturo and his colleagues [Citation25] revealed that aspirin resistance was positively correlated with fasting blood glucose (r = 0.224, p < 0.001), and glycosylated hemoglobin type A1c (HbA1c) levels (r = 0.297, p < 0.0001) in 108 diabetic patients and 67 no diabetic subjects with impedance platelet aggregometry. Furthermore, Pulcinelli et al. [Citation26] found that in diabetic patients, TXB2 production was significantly correlated with fasting plasma glucose and HbA1c. In the present study, aspirin-resistant patients had higher levels of fasting serum glucose compared with aspirin-sensitive patients by TEG, which may be due to the higher proportion of patients complicated with diabetes in aspirin-resistant group. One excellent review, by Ajjan et al. [Citation10], focused on an interaction between glycation and acetylation of platelet proteins, and suggested that increased glycation of platelet and coagulation factor proteins may interfere with the acetylation process to contribute to aspirin resistance in the presence of diabetes. These studies suggest us that glycemic control in diabetic patients may improve the antithrombotic effects of aspirin and reduce adverse clinical events.
The clinical rate of aspirin-resistant group in the present study is low compared to an expected clinical rate, which may be due to stable conditions of patients from the Wangshoulu area of Beijing and a relatively short follow-up time in the present study. However, the present study showed that the prevalence of cardiovascular related events was higher in patients exhibiting aspirin resistance or semiresponders. Most [Citation5,Citation6,Citation27–29], but not all studies [Citation30–32] have demonstrated an increase in the risk for major adverse events associated with patients defined by aspirin resistance. Three major studies with relatively large sample sizes showed a relation between laboratory aspirin resistance and worse clinical outcomes. The first study was performed by Eikelboom et al. [Citation33], who enrolled 976 patients on aspirin from the population of the Heart Outcomes Prevention Evaluation trial. After a 5-year follow-up period, patients with levels of the urinary 11-dehydro TXB2in the upper quartile had two times higher risk of MI and a 3.5 times higher risk of cardiovascular death compared with those in the lower quartile. In the second study, Gum et al. [Citation5] enrolled 326 stable cardiovascular patients on aspirin and tested for aspirin sensitivity by LTA. After a mean follow-up of 679 ± 185 days, aspirin-resistant patients were associated with an increased risk of death, MI or stroke compared with aspirin-sensitive patients (24% vs 10%, HR = 3.12, p = 0.009). In the third study, Chen et al. [Citation6] found a 27.4% prevalence of aspirin resistance as measured by VerifyNow Aspirin with an Aspirin Reaction Unit ≥ 550 in 468 stable CAD patients on aspirin 80–325 mg daily. After a mean follow-up of 379 ± 200 days, patients with aspirin resistance were associated with a significant increase in the composite outcome compared to patients who were aspirin-sensitive (15.6% vs 5.3%, HR = 3.12, p < 0.001). Recently, several meta-analyses revealed that aspirin-resistant patients were associated with a significant increase in the occurrence of adverse clinical events and the resulting odds ratio was from 1.63 to 3.8 [Citation9,Citation34–36]. The present study also showed that aspirin resistance or semiresponders were associated with an increased risk of worse clinical events. However, Kojuri et al. [Citation30] investigated the relationship between aspirin resistance and clinical outcome in 106 stable outpatients six months after successful percutaneous coronary angioplasty. Kojuri et al., using 10 µmol/L ADP-induced aggregation with LTA to define aspirin resistance, found that aspirin resistance was not associated with a significant increase in the composite end points of MI, death, unstable angina or need for revascularization. In addition, there were two studies in relatively small sample size that also revealed that the risk of worse clinical events was not significantly increased in CVD patients with aspirin resistance evaluated by PFA-100 (n = 71, n = 97, respectively) during 2.5–4 years of follow-up [Citation31,Citation32]. These negative results may possibly have been due to a small sample size. In the present study, we found that a negative association between aspirin resistance and clinical outcomes in elderly patients with a median follow-up of 1.5 years. Nevertheless, we kept up following up our participants and found that there were positive results with a median follow-up of 1.8 years. In addition, the prevalence of clinical events in patients with aspirin resistance shows an increased trend with increased follow-up time [Citation5,Citation6,Citation27,Citation37].These changes suggest us that the follow-up time may play an important role in finally clinical outcomes. We should pay more attention to the follow-up time in clinical studies of aspirin resistance, and a relatively long period of follow-up is needed.
There are several possible therapeutic options for patients who experience an adverse event while on aspirin. First, careful clinical judgment is required to assess compliance, stop smoking and interacting medications. Clinicians must emphasize these factors and educate patients with poor compliance [Citation11,Citation13]. Second, aspirin may be switched to clopidogrel, prasugrel or cilostazol, which have been found to result in decreased rates of clinical events in CVD patients [Citation38–40]. Alternatively, the physician may add clopidogrel or other antiplatelet drugs to aspirin. Several studies demonstrated that the addition of clopidogrel to aspirin provides greater platelet inhibitory effects and can overcome aspirin resistance [Citation33,Citation41]. Recently, two studies suggested that statins therapy may improve antiplatelet effect of aspirin [Citation42,Citation43]. Increasing the dose of aspirin may possibly reduce nonresponse or overcome the low response to aspirin in individual patients [Citation23]. However, a large meta-analysis reported that daily aspirin doses of 75–150 mg are an effective antiplatelet regimen as well as higher doses for long-term use [Citation4]. Further studies are needed to focus on the relationship between aspirin dose, clinical events and platelet inhibition.
Previous study reported that 33% of cardiovascular patients were not adherent with their medications, suggesting that cardiovascular patients discontinuing to use their regimens are not uncommon [Citation44]. A multivariable survival analysis demonstrated that stopping aspirin medication was associated with higher mortality (HR 1.82; 95% CI: 1.09–3.0). Additionally, Schwartz et al. [Citation45] revealed that 9% were aspirin resistant because of noncompliance in 191 post-MI patients. In the present study, 4.5% of patients were aspirin resistant due to poor compliance and were excluded from this study. We should not ignore noncompliance in CVD patients taking aspirin therapy.
The present study had one important limitation. The prevalence of aspirin resistance in elderly male patients with CVD was valid for the dose of 75–100 mg/day of aspirin, but we did not investigate the other suggested doses of 162 mg/day and 325 mg/day.
In conclusion, these findings suggest that a significant number of elderly male patients is resistant to aspirin therapy. The prevalence of cardiovascular related events demonstrates an increasing trend in patients with aspirin resistance or aspirin semiresponders. These findings suggest that aspirin-resistant patients may not benefit from antiplatelet therapy with aspirin alone or low-dose aspirin. We should pay more attention to these patients and try to improve the antiplatelet effects for them.
Declaration of Interest: This work was supported by the Military Healthcare Fund of China (07BJZ01) and the Ministry of Science and Technology of China (2009BAI86B04).
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