Federal mandate prohibits denial of any drug, device, or biological product fully approved by the FDA as investigational for the Federal Employee Program (FEP). In these instances coverage of these FDA-approved technologies are reviewed on the basis of medical necessity alone. Call the BCBSMT FEP Customer Service Department at 1-800-634-3569 for benefit information.
Identifying aspirin nonresponders and achieving appropriate levels of platelet inhibition with alternative or additive platelet therapy are the basis of ongoing clinical investigation. In their review of aspirin and clopidogrel resistance, Michos et al. stated that no consensus exists regarding the reference standard for measuring platelet activation, and definitions of aspirin and clopidogrel resistance differ, depending on which test is used. They concluded that “many issues remain unresolved regarding the definition, identification, and clinical importance of resistance to aspirin and clopidogrel. Given these limitations, no established consensus exists of whether aspirin- or clopidogrel-resistant patients should discontinue their antiplatelet regimen or whether additional therapy should be added. Future studies will establish whether patients receiving antiplatelet agents should undergo platelet function studies to assess the adequacy of therapy and determine which antiplatelet drug, or combination thereof, is most efficacious.”
Krasopoulos, Buchanan et al. conducted a meta-analysis and systematic review to determine if there is a relationship between aspirin resistance and clinical outcomes in patients with cardiovascular disease (CVD). They reviewed 20 studies totalling 2930 patients with CVD. Most studies used aspirin regimens ranging from 75-325 mg daily, and six studies included adjunct antiplatelet therapy. Overall, 810 patients were classified as aspirin resistant. Aspirin resistant patients did not benefit from other antiplatelet treatment. The study concluded that patients who are resistant to aspirin are at a greater risk of clinically important cardiovascular morbidity long term than patients who are sensitive to aspirin. In a reported interview about the study, Buchanan acknowledged that while proof of the link between aspirin nonresponsiveness and clinical events is growing, no one knows what to do about it—aspirin sensitivity can be tested for, but there are no data suggesting a course of action.
Eikelboom et al. studied whether aspirin resistance, defined as failure of suppression of thromboxane generation, increases the risk of CV events in a high-risk population. Baseline urine samples were obtained from 5529 Canadian patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Using a nested case-controlled design, urinary 11-dehydo-TXB2 was measured as a marker of in vivo thromboxane generation in 488 patients treated with aspirin who had MI, stroke, or CV death during five years of follow up, and in 488 sex- and age-matched control subjects who were also receiving aspirin but did not have an event. After adjustment for baseline differences, the odds for the composite outcome of MI, stroke or CV death increased with each increasing quartile of 11-dehydo-TXB2, with patients in the upper quartile having 1.8 times-higher risk than those in the lower quartile. The study concluded that in aspirin treated patients, urinary concentrations of 11-dehydo-TXB2 predict the future risk of MI or CV death, and that these findings raise the possibility that elevated urinary 11-dehydo-TXB2 levels identify patients who are relatively resistant to aspirin and who may benefit from additional antiplatelet therapies or treatments that more effectively block thromboxane production or activity. However, Martin et al. reviewed this study and stated that this was a retrospective case-controlled study in which the frequencies of significant risk factors for CVD (obesity, coronary artery disease, peripheral artery disease, hypertension, diabetes, and smoking) were higher in the case group than in the controls and, as such, the reported event risk may be inflated and should be used cautiously as a basis for therapeutic decision-making.
Eikelboom et al. published a later study in which they aimed to determine the external validity of the association of elevated urinary 11-dehydo-TXB2 with increased risk of CV events in aspirin-treated patients enrolled in the Clopidogrel for High Atherosclerotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial, and to determine whether there are any modifiable factors or interventions that lower 11-dehydo-TXB2 concentrations and could thereby reduce risk. They concluded that in aspirin-treated patients, urinary concentrations of 11-dehydo-TXB2 are an externally valid and potentially modifiable determinant of stroke, MI, or CV death in patients at risk for atherothrombotic events, and that “the effectiveness and safety of high-dose aspirin (300-325 mg/day) compared with lower doses (75-100 mg/day) is currently undergoing evaluation in a prospective trial. The potential for statins to mediate some of their favorable effect on vascular events by lowering urinary 11-dehydo-TXB2 is intriguing and worthy of further study.”
McGlasson and Fritsma conducted a study to compare the ability of four commercial platelet function assays (including VerifyNow and urinary 11-dehydo-TXB2 tests) to detect aspirin response in 50 normal individuals taking 81 or 325 mg aspirin in a single-dose response and then in a 7-day dosing regimen. The individuals were not consistently identified as aspirin responsive across all platforms; all assays discriminated between platelet response and nonresponse to aspirin at both dosages. They concluded that it may be necessary to employ multiple assays to detect individual platelet response.
The US National Institutes of Health is funding the PLARAS study (Platelet Hyperreactivity to Aspirin and Stroke), which is currently recruiting participants. VerifyNow and AspirinWorks (11-dehydo-TXB2) are two of the platelet tests being used in the study. Study questions include:
- What is the real prevalence of platelet “resistance” to aspirin during the acute phase of stroke and after one year, as measured using different platelet function tests?
- Do all methods measure similar levels of resistance, or are some methods more sensitive than others?
- Does this resistance result in a worse clinical prognosis? Is this result independent of other variables?
In 2009, Muir et al. published a study they conducted to characterize the prevalence of aspirin resistance in patients with ischemic heart disease, and to investigate the concordance and repeatability of these tests. Consecutive outpatients (n = 172) with stable ischemic heart disease were enrolled. They were started on 150 mg of aspirin daily (day 0), and had platelet function assessment and quantitative analysis at day > or = 7 and then at a second visit about two weeks later. The tests used were optical platelet aggregometry (OPA), platelet function analyzer (PFA-100), and TXB2 metabolites. The study found poor association between PFA-100 and OPA, and between TXB2 metabolites and platelet function tests, and concluded that the prevalence of aspirin resistance is dependent on the method of testing. Response varies on a temporal basis, indicating that testing on a single occasion is inadequate to diagnose resistance or guide therapy in a clinical setting.
In their review of aspirin resistance, Gurbel and Tantry of the Sinai Center for Thrombosis Research in Baltimore, Maryland, acknowledge that laboratory evaluation of platelet response has identified response variability, nonresponsiveness or resistance in selected patients, and that some studies have correlated this resistance to the occurrence of thrombotic events. However, at this time specific treatment recommendations are not established for patients exhibiting resistance during aspirin therapy.
A search of peer reviewed literature through February 2012 identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy.
Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.