This study reports distinctive findings on the prevalence of inadequate platelet inhibition in patients with a coronary stent who are prescribed clopidogrel and return to a community hospital emergency department with chest pain. Depending on the definition of inadequate platelet inhibition used, 42%–54% of such patients had poor inhibition of platelet function. This is a remarkable failure of efficacy of a drug treatment strategy. Whether or not these patients prove to have an acute coronary syndrome at the time of the emergency department visit, or chest pain of other etiology, this determination of the efficacy of the current treatment strategy produces results that are concerning. The quantitative analysis of inadequate platelet inhibition varies somewhat, depending on whether percent inhibition or PRU is the metric, although concordance is reasonable ().
Noncompliance with medication may have contributed to inadequate platelet inhibition. The incidence of non adherence with dual antiplatelet therapy in the “real-world” international observation registry was 2% at 30-day follow-up.19
Nonetheless, the current study does provide a distinctive analysis of the incidence of adequate and inadequate platelet inhibition in a group of patients with coronary stents and chest pain, and such patients are commonly seen in emergency departments.
The individual biological response to clopidogrel is variable. Multiple studies support the hypothesis that this variable pharmacodynamic effect of clopidogrel may be responsible for atherothrombotic events following stent deployment.9
Diabetes and African American race were strong predictive factors. Hyporesponsiveness to clopidogrel can be secondary to several factors, including age, body mass index, diabetes, dyslipidemia, chronic renal disease, genetic polymorphism, and pharmacokinetic and pharmacodynamic interactions arising from concomitant use of other drugs.23
Failure to take the drug as prescribed certainly can produce hyporesponsiveness. Studies have found that platelets from diabetic patients are generally more reactive25
and less responsive to antiplatelet therapy.27
Our findings are consistent with those observations. Several factors may explain this global hyper-reactive platelet in diabetes, such as insulin resistance, poor glycemic control, increased inflammatory status, increased response to ADP, increased reactivity on contact with collagen,28
increased fibrinogen levels,29
and increased production of epinephrine and thrombin receptor agonist peptide.28
Mangicapra et al used the VerifyNow assay in diabetic patients undergoing percutaneous coronary intervention and found them to have higher platelet reactivity and worse periprocedural outcomes.31
Diabetic patients also have a poor response to aspirin (aspirin reaction units > 550).32
In our study, patients with type 2 diabetes presenting with chest pain had a higher prevalence of hyporesponsiveness (adjusted OR = 2.1409), as shown in .
This analysis also shows a greater risk of hyporesponsiveness in African American patients than in non-African Americans (adjusted OR = 2.165). Collins et al33
have shown the African American race to be an independent risk factor for developing stent thrombosis after placement of a drug-eluting stent. Despite higher compliance with clopidogrel in African American patients, they were nearly three times more likely to develop stent thrombosis than non-African Americans (1.71% versus 0.59%). However, no platelet function testing was done in these patients to probe any relationship between stent thrombosis and hyporesponsiveness despite higher compliance with clopidogrel. Higher stent thrombosis may be due to genetic polymorphism making African American patients less responsive to clopidogrel.
As suggested by this and other studies, mechanisms of hyporesponsiveness to clopidogrel, such as genetic polymorphism, may need to be assessed. Previous studies have demonstrated that carriers of the cytochrome P450 (CYP) 2C19 hypofunctioning allele may produce a factor leading to decreased clopidogrel metabolites, causing diminished platelet inhibition and an increased rate of cardiovascular events.34
Such polymorphism is seen more frequently in African American and East Asians than in Caucasians.36
The CYP 2C19*2 allele is present in 13% of Caucasians, 18% of African Americans, and 29% in East Asians.37
Rapid point-of-care genotyping at the bedside is evolving in clinical practice, which will help personalization of antiplatelet therapy.38
While the importance of the platelet function assay is evolving, the platelet function test may be useful in high-risk patients, such as those with diabetes, left main stem stenosis, and diffuse atherosclerotic disease with complex coronary lesions undergoing percutaneous coronary intervention.39
Limitations of this study include its lack of clinical outcome data or biomarkers for ischemia. Because inclusion in the study was dependent on the patient stating that they were taking clopidogrel and aspirin, the level of actual, as opposed to stated, patient compliance with the antiplatelet regimen is not known. Therefore, this was not a study of drug efficacy but rather a study of platelet inhibition in the clinical syndrome of chest pain evaluated in the emergency department for patients who have been prescribed clopidogrel and aspirin.
Tailoring antiplatelet therapy according to platelet function testing
Use of the platelet function assay to guide antiplatelet therapy has received considerable attention. This study and others have identified clinical risk factors for inadequate platelet inhibition by clopidogrel. However, clinical profiling clearly has inadequate predictive value in itself, and a platelet function assay may add value. Results from the large ADAPT-DES (Assessment of Dual AntiPlatelet Therapy With Drug Eluting Stents) registry suggest that hyporesponsiveness to clopidogrel after implantation of a drug-eluting stent is an independent predictor of stent thrombosis and myocardial infarction.40
A platelet function assay may help screen for hyporesponders and nonresponders, and could also identify patients in whom medication compliance may be the main issue.
There are several alternatives to clopidogrel for patients with a suboptimal response to antiplatelet therapy. Newer antiplatelet agents, such as prasugrel and ticagrelor, have demonstrated superiority in patients with an acute coronary syndrome.41
These new drugs are not affected by genetic variants of CYP 2C19, and are more effective, with a more predictable pharmacodynamic response, than the standard dose of clopidogrel. However, it is likely that clopidogrel will remain a valuable and widely used inhibitor of platelet function. This study demonstrates that the therapeutic goal, ie, platelet inhibition, assessed by an in vitro assay, is not achieved by a large proportion of patients prescribed clopidogrel to prevent coronary stent thrombosis. Ongoing trials will expand our understanding of dual antiplatelet regimens and the role of the platelet function assay. The use of in vitro testing may be useful to guide treatment and to identify hyporesponders or nonresponders.