Original Contribution

Platelet aspirin resistance in ED patients with Suspected acute coronary syndrome^?,??

Jonathan Glauser MD ^a,?, Charles L. Emerman MD ^b, Deepak L. Bhatt MD ^c, W. Frank Peacock IV MD ^a

^aCleveland Clinic, Case Western Reserve University, Cleveland, OH, USA ^bMetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA ^cVA Boston Health Care System, Boston, MA, USA

Received 29 December 2008; accepted 6 January 2009

Abstract

Background: Platelet aspirin resistance is reported to be as high as 45%. The prevalence of emergency department (ED) platelet aspirin resistance in suspected acute coronary syndrome (ACS) is not described. Our purpose was to determine the prevalence of platelet aspirin resistance.

Methods: We determined platelet aspirin resistance in a convenience sample of ED suspected ACS patients. Eligible patients had longer than 10 minutes of chest pain or an ischemic equivalent. Two hours after receiving 325 mg of aspirin, blood was assessed for Platelet function (Accumetrics, San Diego, CA). Definitions are as follows: aspirin resistance, at least 550 aspirin reaction units; positive troponin T, greater than 0.1 ng/mL; significant coronary lesion, at least 70% stenosis. The composite end point was prospectively defined as a 30-day revisit, positive cardiac catheterization, or hospital length of stay longer than 3 days.

Results: Of 200 patients, 50.5% were male, 50.0% were black, troponin T was positive in 7.5%, cardiac catheterization was done in 10.5%, and 33.3% had a Significant stenosis. Final diagnoses were noncardiac in 83.4%, stable angina in 8.0%, and unstable angina in 8.5%. Overall, 6.5% were resistant to aspirin; and high- risk patients trended to more aspirin resistance than non-high-risk patients (23.1% [3] vs 9.1% [17]; P value 95% confidence interval [CI], -0.0929 to 0.373). one-month follow-up found ED revisits in 12.5% of aspirin-resistant vs 4.9% of non-aspirin-resistant patients (95% CI, -0.114 to 0.182) and rehospitalization in 12.5% of resistant patients vs 4.3% of nonresistant patients (P value 95% CI, -0.108 to 0.187). Although LOS was similar at index admission, if rehospitalized, LOS was 6.5 for aspirin-resistant patients vs 3.2 days in nonresistant patients (P b .0001).

Conclusion: This first report of platelet aspirin resistance in patients presenting to the ED with suggested ACS finds that it is present in 6.5% of patients.

(C) 2010

^? Dr Bhatt has served as a consultant for the following: Arena, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardax, Centocor, Cogentus, Daiichi- Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, McNeil, Medtronic, Millenium, Molecular Insights, Otsuka, Parigenix, PDL, Philips, Portola, Sanofi-Aventis, Schering-Plough, Scios, Takeda, The Medicines Company, and Vertex.

^?? Dr Peacock is on the Scientific Advisory Board of the following companies: Abbott, Beckman-Coulter, Biosite, Inovise, Inverness, Otsuka, Ortho

Clinical Diagnostics, and The Medicines Company. He has Research Grants from the following: Abbott, BAS, Biosite, Brahms, CHF Solutions, Heartscape, Inovise, Inverness, PDL, and The Medicines Company. He has an ownership interest in Vital Sensors.

* Corresponding author. Institute of Emergency Medicine, The Cleveland Clinic, Cleveland, OH, 44195, USA. Tel.: +1 216 445 4550.

E-mail address: [email protected] (J. Glauser).

0735-6757/$ - see front matter (C) 2010 doi:10.1016/j.ajem.2009.01.004

Introduction

Antiplatelet therapy is a cornerstone of cardiovascular medicine. Clinical trials have shown the efficacy of aspirin in the primary and secondary prevention of myocardial infarction, stroke, and Cardiovascular death [1]. However, during long-term follow-up, recurrent vascular events occur in 10% to 20% of patients treated with aspirin [2]. The term aspirin resistance has been used to describe the occurrence of cardiovascular events such as recurrent myocardial infarction, stroke, or death in patients despite their compliance with regular intake of aspirin [3,4].

Aspirin resistance as a laboratory phenomenon is diagnosed where there is the inability of aspirin to inhibit one or more tests of aspirin function. The prevalence of aspirin resistance varies widely, depending upon the test used. It has been cited to be as low as 0.4% and as high as 45% [5,6]. Depending on the test used, the number of Americans on long-term Aspirin therapy who are aspirin resistant could be as few as 120 000 or as many as 10.5 million [7].

Aspirin-resistant patients have platelets that are not affected in the same way as the platelets of those who benefit from aspirin therapy (aspirin “sensitive” patients).

Because there are an estimated 8 million annual US emergency department (ED) patients who present with chest pain, knowledge of the rate of aspirin resistance in ED suspected acute coronary syndrome (ACS) patients would allow the design of appropriate interventional studies to combat this potential public health challenge.

No ED study has prospectively determined the rate of aspirin resistance in patients presenting to the ED with suspected ACS. Our purpose was to determine the rate of aspirin resistance in patients presenting to the ED with suspected ACS.

Methods

We used a convenience sample of patients presenting to the ED with suspected ACS. Screen failures and consent failures were not recorded. Suspected ACS was defined by the attending ED physician. Patients were enrolled when Research staff was available (from 7:30 AM to midnight of the standard 5-day work week). Eligible patients had at least 10 minutes of chest pain or what was felt to be an ischemic equivalent by the attending physician within 24 hours of their ED presentation. Chief complaints were categorized as chest pain, shortness of breath, syncope, or other myocardial ischemic equivalent.

Eligible patients were required to provide informed consent and give blood sample for aspirin resistance measurement. Patients were excluded if they had a prior history of aspirin allergy or an underlying medical pathology that would preclude their being alive and able to be contacted by phone within 30 days of hospital discharge. If all

inclusion and no exclusion criteria were met, patients received 325 mg of oral acetylsalicylic acid that was swallowed (not chewed) with sips of water. Two hours after receiving the aspirin dose, aspirin resistance was measured. The results of aspirin resistance testing were blinded to all staff caring for the patient.

Platelet aspirin resistance, alternatively termed nonre- sponse or low response to aspirin, was determined by using a point-of-care platelet function assay. The VerifyNow Aspirin Assay (Accumetrics, San Diego, CA) is a point-of- care, rapid optical platelet function test that measures the agglutination of fibrinogen-coated beads in response to arachidonic acid stimulation in whole blood. If aspirin produces the expected antiplatelet effect, platelets do not aggregate; and the fibrinogen-coated beads will not agglutinate, causing minimal increase in light transmission. Conversely, if there is little or no response to aspirin, the platelets will aggregate; and light transmission will increase. Testing results are calculated from the change in the optical signal caused by the aggregation and are expressed as aspirin reaction units. Aspirin resistance is defined as a result of greater than 550 aspirin reaction units [8]. The prevalence of aspirin resistance varies widely depending upon the test used, so no criterion standard can be said to exist currently. The VerifyNow Aspirin Assay has demonstrated excellent correlation with optical aggregometry, a test that gives relatively low rates for aspirin resistance [4,7].

We defined a positive troponin T (TnT) as at least 0.1 ng/ mL in the absence of renal failure; and if the patient underwent cardiac catheterization, a significant coronary lesion was defined as at least 70% stenosis. The primary end point was a composite of 30-day revisit, positive cardiac catheterization, or Hospital length of stay longer than

3 days. Follow-up was determined by inpatient medical record review for hospital outcomes and by telephone contact with the patient at 30 days post-ED visit. No patients were lost to follow-up.

Data were analyzed using SAS (Cary, NC) version 9.0. The ?2 test was used for categorical data; the Student t test, for linear data. ? was defined as .05. This study was approved by the institutional review board. Accumetrics provided the point-of-care assay and financial support for data collection by study nurses. The authors wrote the paper, performed the statistical analysis, and had control of the data throughout the entire study. Accumetrics did not provide any other support, nor did their personnel have any input into the analysis or preparation of the manuscript.

Results

There were 200 patients who met all inclusion and no exclusion criteria. Of these, 50.5% were male, 50.0% were black, and 46.5% were white. The overall mean age was

59.7 +- 13.3 years, with a chief complaint of chest pain in 175

(87.5%), “other” in 12 (6.0%), shortness of breath in

8 (4.0%), and syncope in 4 (2.0%); the chief complaint in 1 (0.5%) patient was not recorded. cardiac risk factors were present in the following distribution: 54 (26.8%) had known coronary artery disease, a family history of coronary artery disease was present in a primary relative in 34 (16.9%), 56 (27.9%) had known hyperlipidemia, 56 (27.9%) had

diabetes, 139 (69.1%) were hypertensive, and 45 (22.4%) admitted to current smoking of tobacco products.

Of the overall group, 15 (7.5%) had a myocardial infarction diagnosed by an elevated troponin during their hospitalization. Cardiac catheterization was performed in 21 (10.5%); and of these, 7 (33.3%) were found to have a coronary diameter stenosis of at least 70%. The final diagnosis demonstrated a confirmed ACS rate of 16.6% and is similar to contemporary ED practice [9]. At the end of hospitalization and 30-day follow-up, the final diagnoses were noncardiac in 166 (83.4%), stable angina in 16 (8.0%),

and unstable angina in 17 (8.5%).

Aspirin resistance occurred in 13 (6.5%) patients in the entire cohort. When stratified by aspirin resistance, there was no statistical difference in regard to sex. The rate of occurrence of the composite end point trended higher in aspirin-resistant patients than the group without aspirin resistance (23.1% [n = 3] vs 9.1% [n = 17]; P with 95% confidence interval [CI], -0.0929 to 0.373). One-month follow-up found ED revisits in 12.5% (n = 1) in the aspirin- resistant cohort compared with 4.9% (n = 8) of the subset without aspirin resistance (P with 95% CI, -0.114 to 0.182). Rehospitalization was also more common in the patients with aspirin resistance (12.5%, n = 1) vs patients without aspirin resistance (4.3%, n = 7) (P with 95% CI, -0.108 to 0.187). There was no LOS difference at index admission between the patients with aspirin resistance and those without aspirin resistance. However, if rehospitalized within 30 days, the mean LOS for 1 patient was 6.5 days in the aspirin-resistant cohort, compared with 3.2 days in the 7 patients without aspirin resistance.

Discussion

We found that aspirin resistance occurred in 6.5% of patients presenting to the ED with suspected ACS. Although this rate is considerably lower than those of other investigations, if applied across the cohort of patients presenting to the ED with suspected ACS, this suggests that the 1.2 million patients presenting with new and recurrent angina pectoris and the 920 000 patients with new and recurrent myocardial infarction in the United States annually-or approximately 2.1 million total patients per year-may not receive the full benefit reported with aspirin use in ACS [10]. Based upon historical data citing a 23% 5- week vascular mortality reduction in patients with suspected acute myocardial infarction treated with aspirin [11] and

Canadian data demonstrating a 71% reduction in mortality after 18 months of therapy for Non-ST elevation ACS [12],a loss of aspirin’s protective effect potentially can affect thousands of lives annually. Future studies examining strategies to overcome aspirin resistance in the ED will require knowledge of these data to be adequately powered to determine relevant clinical outcomes.

Others have examined the occurrence of adverse events and aspirin resistance in non-ED populations. One study in 1993 was among the first to report a relationship between aspirin resistance and adverse vascular events. platelet reactivity was measured in 90 stroke survivors. Patients were treated with 500 mg aspirin 3 times a day and followed for 24 months. The major end points of stroke, myocardial infarction, or vascular death occurred during follow-up in 4.4% of aspirin responders and 40% of aspirin nonrespon- ders (P b .0001) [13].

A recent meta-analysis of 20 studies totaling 2930 patients with cardiovascular disease identified 810 patients who were aspirin resistant. Patients resistant to aspirin were found to be at a significantly greater risk for cardiovascular morbidity long term and for death than patients sensitive to aspirin. Aspirin resistance appeared to be less prevalent in men than in women and higher in patients with previous Renal impairment. Platelet inhibitors such as clopidogrel and tirofiban did not provide any benefit to aspirin-resistant patients [14].

The aspirin resistance test we used for this study evaluates aspirin resistance by platelet agglutination of fibrinogen- coated beads in response to propyl gallate or arachidonic acid stimulation. This was chosen because it is available as a bedside point-of-care methodology that allows early ED results and the opportunity for interventions if warranted by future research. Other methods to evaluate aspirin resistance exist. Aspirin (acetylsalicylic acid) reduces the activation of platelets by irreversibly acetylating cyclooxygenase-1 (COX-1) and thereby reduces thromboxane A2 produced by platelets [15]. One common definition of aspirin resistance is the inability of aspirin to inhibit platelet thromboxane A2 production or to inhibit tests of platelet function that are dependent upon platelet thromboxane production [16,17]. This is most directly demonstrated through the ability of aspirin to inhibit arachidonic acid- induced platelet activation and aggregation via aspirin’s inhibitory effect on platelet COX-1 activity [18]. Other platelet tests use different technology including shear stress- induced platelet activation, light transmission through a suspension of platelet-rich plasma exposed to other agents, or platelet-dependent hemostasis.

Other studies have examined outcomes in patients with platelet aspirin resistance. These include 468 stable coronary artery disease patients followed for 379 days. The aspirin- resistant group was more likely to suffer cardiovascular death, myocardial infarction, stroke, unstable angina, or transient ischemic attack (odds ratio [OR], 2.5) [19]. In a case series of 326 stable cardiovascular disease patients, the 17

(5.2%) with aspirin resistance had a greater composite end point of death, myocardial infarction, or stroke after a mean follow-up of 1.9 years (24% vs 10%) [20]. Finally, in a cohort of 151 patients undergoing percutaneous coronary intervention (PCI) treated with 80 to 325 mg/d aspirin for 1 week and 300 mg clopidogrel within 24 hours of the procedure, the 19% with aspirin resistance had more post- PCI creatine kinase-MB and cardiac Troponin elevations (odds ratio, 2.5; 95% CI, 1.2-6.9) [21].

There is evidence that the dose of aspirin affects the prevalence of aspirin resistance. Some reports cite the prevalence of aspirin resistance when the aspirin dose was 161 mg/d or less [7]. One report using optical aggregometry noted a prevalence of 9% aspirin resistance when a dose of

81 to 325 mg/d was used [22]. Others have noted a prevalence of aspirin resistance of less than 1% in patients taking 325 mg/d. Of 203 patients undergoing PCI studied, aspirin resistance was noted in 7 of these patients. All were aspirin sensitive after in-hospital aspirin treatment [23].

The prevalence of aspirin resistance has been reported to be increased in women [21]; in patients with congestive heart failure, ACS, hypercholesterolemia [4], renal insufficiency, or Insulin-dependent diabetes mellitus; and in smokers [7,24]. Although there is no identified treatment yet for failed antiplatelet therapy, an initial approach to therapy might include optimal control of glucose and cholesterol levels [4].

Several biologic mechanisms for aspirin resistance have been proposed. Some patients may have increased platelet activation that could override the inhibitory effect of aspirin, demonstrating nonresponse to clopidogrel as well [25]. Genetics may play a role in patient response to aspirin, as polymorphisms of platelet glycoproteins and of von Will- ebrand Factor have been postulated to cause aspirin resistance [26,27].

Platelet function inhibition may be a matter of degree, rather than an “all or none” phenomenon. Patients with aspirin resistance may have more advanced atherosclerosis or perhaps more macrophages in their atherosclerotic plaques, which may produce thromboxane. It is possible that aspirin has antithrombotic effects unrelated to its COX- 1-dependent inhibition of platelet function [18,26].

Some importance has been placed on substrate competi- tion at COX-1 receptors by other nonsteroidal anti- inflammatory drugs (NSAIDs). Ibuprofen, for example, can adhere to the COX-1 binding site of aspirin and, via steric hindrance, prevent aspirin from exerting its antiplatelet effect and limit its cardioprotective function [4]. If arachidonic acid displaces NSAID at COX-1, aspirin resistance may be imitated in patients taking NSAIDs at the same time they are taking acetylsalicylic acid [28]. In states such as sepsis or disseminated intravascular coagulation in which a highly increased production of platelets is induced, some very young, aspirin resistance is simulated [28].

Noncompliance may be a factor as well. Compliance with aspirin therapy was not confirmed by Salicylate levels in any

of the aforementioned studies [7]. Many patients found to be aspirin resistant admitted they were not taking the prescribed aspirin [23,29]. On the other hand, a large case-control study measured urinary 11-dehydrothromboxane B2 levels, a marker of in vivo thromboxane generation, in patients enrolled in the Heart Outcomes Prevention Evaluation study. Patients with levels of urinary 11-dehydrothromboxane B2 in the upper quartile, indicating relative aspirin resistance, had a higher risk of a myocardial infarction, stroke, or death than those in the lowest quartile (odds ratio, 1.8; 95% CI, 1.2-2.7) [30].

It is difficult to ascertain the exact prevalence of aspirin resistance in the general population. Different agonist concentrations, measuring times, sample volumes, and platelet numbers in platelet-rich plasma have been used, even when the same method was applied, precluding direct comparisons; so the prevalence of aspirin resistance in the general population is unknown. Data regarding the pre- valence of aspirin resistance vary between 5% and 60%. It may be best to view aspirin resistance measurements as a continuous variable, akin to blood pressure [4,28]. Finally, although the objective term aspirin resistance is a measur- able laboratory phenomenon, treatment failure after the use of aspirin is a clinical observation. This latter can be defined operationally as the failure of aspirin to prevent clinical atherothromboembolic Ischemic events.

Limitations

Our analysis is limited by its sample size. This was a pilot study. Although we have found a low rate of platelet aspirin resistance, knowledge of the ED rate of aspirin resistance will allow future studies to be appropriately powered to evaluate clinical and Treatment outcomes. Patients too ill to be contacted by phone, for example, those with metastatic Lung cancer, who inevitably increase the rate of loss to follow-up and thus do not contribute to an understanding of the pathophysiology of platelet resistance, were excluded. Furthermore, our analysis represents a single-center experi- ence, at an institution with a high rate of coronary vascular disease. Future multicenter research is needed to determine if our rate of platelet aspirin resistance is duplicated by other institutions with a lower prevalence of coronary artery disease presentations. Finally, because of our small sample size, we cannot comment on the clinical impact of therapy in patients with known platelet aspirin resistance and what therapy should be instituted if a patient is found to have aspirin resistance.

Conclusion

This first report of platelet resistance in patients presenting to the ED with suspected ACS finds that it is

present in 6.5% of patients. Future studies will require knowledge of this baseline frequency to be adequately powered to determine outcomes associated with this biologic information. Whether this frequency of aspirin resistance represents a large population at risk for inadequate or incorrect therapy, or if interventions can ameliorate this risk is unknown.

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