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Keywords:

  • aspirin resistance;
  • atherothrombosis;
  • low-dose aspirin;
  • platelet COX-1;
  • primary prevention

Abstract

  1. Top of page
  2. Abstract
  3. The optimal dose
  4. Aspirin ‘resistance’
  5. Balance of benefits and risks
  6. Future directions
  7. Acknowledgments
  8. Disclosure of Conflict of Interests
  9. References

Summary.  Although conceived at the end of the 19th century as a synthetic analgesic agent with improved gastric tolerability vs. naturally occurring salicylates, acetylsalicylic acid (marketed as aspirin in 1899) turned out to be an ideal antiplatelet agent about 90 years later, following the understanding of its mechanism of action, the development of a mechanism-based biomarker for dose-finding studies, and the initiation of a series of appropriately sized, randomized clinical trials to test its efficacy and safety at low doses given once daily. At the turn of its 110th anniversary, aspirin continues to attract heated debates on a number of issues including (i) the optimal dose to maximize efficacy and minimize toxicity; (ii) the possibility that some patients may be ‘resistant’ to its antiplatelet effects; and (iii) the balance of benefits and risks in primary vs. secondary prevention.


The optimal dose

  1. Top of page
  2. Abstract
  3. The optimal dose
  4. Aspirin ‘resistance’
  5. Balance of benefits and risks
  6. Future directions
  7. Acknowledgments
  8. Disclosure of Conflict of Interests
  9. References

The consistency of dose requirement and saturability of the effects of aspirin in acetylating platelet cyclooxygenase (COX)-1, inhibiting thromboxane (TX)A2 production, and preventing vascular complications constitutes the strongest evidence that aspirin prevents atherothrombosis through selective, cumulative inhibition of platelet TXA2 production [1]. Therefore, it is likely that any of the dose-dependent effects of aspirin on other determinants of arterial thrombosis is much less important than the virtually complete suppression of platelet COX-1 activity that is achieved upon once daily dosing with as low as 30 mg [1,2].

Although a widespread consensus exists in defining a relatively narrow range of recommended doses, i.e. 75–100 mg daily, for the long-term prevention of myocardial infarction (MI) and stroke [1], the optimal dose issue has been resurrected by the increasing popularity of aspirin ‘resistance’ [3] (see below).

The current attitude in some circles (e.g. interventional cardiology and some neurological enclaves) tends to overemphasize additional antiplatelet effects of higher doses of aspirin, while dwarfing the importance of dose-dependent gastrointestinal (GI) toxicity, and largely ignoring the untoward cardiovascular consequences of dose-dependent COX-2 inhibition [4,5]. The enthusiastic supporters of the concept that ‘more is better’ should be reminded that use of 300–325 mg instead of 75–100 mg daily is known to: (i) cause a more profound inhibition of COX-1 in the GI mucosa, resulting in new mucosal lesions that may eventually bleed; (ii) downregulate the vasodilator effects of endothelial PGI2, resulting in a potential pharmacodynamic interaction with angiotensin converting enzyme inhibitors; and (iii) impair PGI2-dependent thromboresistance, resulting in a potential attenuation of cardioprotection [1,4]. On the other hand, neither head-to-head randomized trials nor indirect comparisons of higher vs. lower doses have ever demonstrated improved efficacy with higher doses and, in fact, the results of both direct and indirect comparisons suggest that the opposite may be true [1].

Thus, the saturability of the antiplatelet effect of aspirin at low doses, the lack of dose–response relationship in clinical trials evaluating its antithrombotic effects, and the dose-dependence of its side-effects all support the use of the lowest effective dose (50–100 mg daily) as the most appropriate strategy to maximize its efficacy and minimize its toxicity [1,6,7].

Aspirin ‘resistance’

  1. Top of page
  2. Abstract
  3. The optimal dose
  4. Aspirin ‘resistance’
  5. Balance of benefits and risks
  6. Future directions
  7. Acknowledgments
  8. Disclosure of Conflict of Interests
  9. References

Low-dose aspirin can prevent one quarter to one third of fatal and nonfatal vascular events in high-risk patients [2]. Patients may experience recurrent events while on aspirin because of the multifactorial nature of atherothrombosis [8]. Such a treatment failure is often inappropriately referred to as aspirin ‘resistance’ [3,9]. This term has been used also to indicate incomplete inhibition of platelet function by low-dose aspirin, with extremely variable estimates of its incidence and inconclusive data on its clinical relevance [9]. The various methods used to quantitate the antiplatelet effect of aspirin (e.g. agonist-induced platelet aggregation) variably reflect the aspirin-sensitive, TXA2-dependent component of platelet aggregation. Moreover, characterization of ‘resistant’ vs. ‘responder’ status is typically based on a single determination of platelet function with the underlying assumption that this captures a stable phenotype [9]. In a recently completed study in healthy subjects, platelet COX-1 activity, as reflected by serum TXB2 levels, was uniformly and persistently suppressed by aspirin 100 mg given daily for 1–8 weeks [10]. However, platelet COX-1 inhibition was not reflected consistently by functional assays, leading to occasional misclassification of ‘responder’ as ‘resistant’ phenotype owing to poor intra-subject reproducibility of platelet aggregation measurements [10]. Thus, in contrast to measurements of serum TXB2 for which every single value of more than 200 samples obtained during aspirin intake was at least 97% lower than baseline values, measurements of various functional indexes categorized according to previously described thresholds of response [9] identified a variable, assay-dependent frequency of ‘nonresponder’ samples, ranging from as low as 1.4% to as high as 30% [10]. However, inspection of prior or subsequent determinations performed in the same subjects clearly identified the inconsistent nature of this apparent ‘nonresponder’ phenotype, making the interpretation of many published studies of aspirin ‘resistance’ a problematic exercise.

The relatively low signal-to-noise ratio and poor intrasubject reproducibility of many platelet function measurements, as well as the non-linear relationship between inhibition of platelet COX-1 activity and inhibition of TXA2-dependent platelet aggregation [10], seriously question the validity of arbitrary functional thresholds widely used for the definition of aspirin ‘resistance’ [9]. We suggest that the adequacy of the antiplatelet effect of aspirin is best reflected by serum TXB2, a mechanism-based biomarker the very high signal-to-noise ratio and reproducibility of which are ideally suited to detect non-compliance as well as a pharmacodynamic interaction with other nonsteroidal antiinflammatory drugs (NSAIDs), i.e. two of the most obvious, but often neglected, causes of less-than-complete inhibition of platelet COX-1 activity in aspirin-treated subjects [1,9].

While genetic, dietary, pharmacologic or disease-related modifications in the molecular target of aspirin could well modify its interaction with the serine529 residue of platelet COX-1, no such mechanistic insight has been provided by hundreds of published papers on aspirin ‘resistance’. Competition by ibuprofen or naproxen for reversible binding of aspirin to arginine120 in the COX-1 channel [1] and the influence of a high peroxide tone on the ability of aspirin to acetylate the enzyme [11] provide interesting mechanistic paradigms of response variability. Furthermore, accelerated renewal of the molecular target, due to enhanced platelet regeneration, might be expected to shorten the duration of irreversible COX-1 inactivation and dictate a different dosing interval. Examples of disease-related modifications of platelet regeneration include diabetes mellitus and essential thrombocythemia (ET).

Furthermore, as TXA2 can be produced, at least in part, via COX-2 in newly formed platelets [12] and inflammatory cells [1], residual TXA2 biosynthesis can be detected in aspirin-treated patients with vascular disease as reflected by the urinary excretion of its major enzymatic metabolites [8]. Thus, additional studies on the mechanisms and clinical relevance of aspirin-insensitive TXA2 biosynthesis are clearly warranted.

Balance of benefits and risks

  1. Top of page
  2. Abstract
  3. The optimal dose
  4. Aspirin ‘resistance’
  5. Balance of benefits and risks
  6. Future directions
  7. Acknowledgments
  8. Disclosure of Conflict of Interests
  9. References

Previous meta-analyses of the effects of antiplatelet therapy among people at high risk of occlusive vascular disease have shown that the benefits of aspirin far exceed the bleeding risks among such patients [1]. In contrast, a majority of participants in the primary prevention trials were at low absolute risk of coronary disease; on average, the annual risk of a vascular event in the primary prevention trials was only about one tenth of that occurring in the high-risk trials [1]. Overall, aspirin reduced major vascular events by 12% in the low-risk trials [13]. This benefit was largely confined to the prevention of non fatal MI, with no statistically significant reductions in stroke or vascular death. The absolute benefits and risks of aspirin in the primary prevention trials were very small. Each year less than one person in every 1000 could expect to avoid an occlusive vascular event by taking aspirin, whilst a comparably small number could expect to experience a major extracranial bleed [13]. The relative size of these opposing effects is too imprecisely known in low-risk people (i.e. <1% per year) to predict the net public health consequences of widespread aspirin use in healthy people. Among people at moderately increased risk of serious vascular events (based on coronary risk >1% per year), the absolute benefits of aspirin might exceed the risks among them. But, as only 8% of the participants were categorized as moderate-risk in the primary prevention trials, the benefits and hazards could only be estimated approximately. Until the benefits of aspirin can be defined more precisely, therefore, the possibility of a benefit does not seem to justify the probability of a hazard. This observation emphasizes the need for trials of aspirin for primary prevention among specific groups at increased risk of vascular disease, such as those aged over 70 years and people with diabetes.

Current clinical practice guidelines typically base recommendations about the use of aspirin in primary prevention on variable (from 0.6% to 2.0% risk per year) and largely arbitrary risk thresholds that are derived from tabular data meta-analyses of primary prevention trials. The limitations of this approach are related to the following facts: (i) the six primary prevention trials of aspirin were initiated 20–30 years ago; thus, estimates of benefit based on the vascular event rate in the control arm of these studies tend to over-estimate the actual size of benefit when aspirin is used in individuals whose modifiable risk factors are more aggressively managed; (ii) individuals at elevated coronary risk may also be at elevated risk of bleeding; moreover, those at higher-than-average bleeding risk (because of advanced age or prior history) were largely excluded from entering aspirin trials; thus, estimates of excess bleeding complications due to aspirin tend to under-estimate hazard in the general population; (iii) most primary prevention trials failed to demonstrate a statistically significant benefit of aspirin on the pre-specified primary end-point (probably because most were underpowered); the substantial uncertainty of these results is reflected in lack of regulatory approval of this indication in many countries (including the USA).

Future directions

  1. Top of page
  2. Abstract
  3. The optimal dose
  4. Aspirin ‘resistance’
  5. Balance of benefits and risks
  6. Future directions
  7. Acknowledgments
  8. Disclosure of Conflict of Interests
  9. References

The last 25 years have witnessed an exponential growth of clinical studies that have established the efficacy and safety of low-dose aspirin in a variety of high-risk patients [1,2]. To address the uncertainty of interventional cardiologists about the optimal dose of aspirin for patients with acute coronary syndromes managed with an early invasive strategy, the CURRENT-OASIS 7 trial is randomizing 18 000–20 000 such patients to receiving a high dose of 300–325 mg or a low dose of 75–100 mg daily for 30 days (all receive a loading dose of at least 300 mg on day 1). Despite 6 randomized trials in approximately 95 000 participants without prior vascular disease, the place of aspirin in primary prevention remains uncertain. The Antithrombotic Trialists’ Collaboration is about to report the results of an individual participant data meta-analysis of these trials that may help in characterizing the balance of benefits and risks in persons at variable baseline coronary risk [13]. Moreover, several additional primary prevention studies are currently ongoing with the aim of recruiting people at relatively high cardiovascular risk (i.e. ≥2% per year), because of diabetes mellitus (ASCEND and ACCEPT-D), advanced age (ASPREE) or a cluster of risk factors that do not include diabetes (ARRIVE).

An increasing number of practicing physicians are being led to believe that aspirin ‘resistance’ is a true clinical diagnosis, requiring a change in antiplatelet therapy (typically an increase in the aspirin dose or a switch to ticlopidine or clopidogrel). In light of the serious methodological limitations noted above and lack of a biologically plausible mechanistic hypothesis, this trend is not justified and may be doing more harm than good. It is hoped that future studies of this ill-defined phenomenon will follow a minimum set of rules to make the results unequivocally interpretable. These should include: (i) repeated rather than single measurements of platelet function; (ii) monitoring of compliance and potential interactions with other NSAIDs, based on serum TXB2 measurements rather than questionnaires; (iii) definition of the intra- and inter-subject variability of the functional assay(s); (iv) analyzing the level of functional response as a continuous variable and not as a dichotomous definition for which there is no apparent justification; and (v) performing a priori sample size calculation, with adequate statistical power to detect a realistic difference in clinical outcomes. The relatively smooth transition from the vaguely defined concept of clopidogrel ‘resistance’ to a satisfactory characterization of the major genetic and pharmacokinetic determinants of the interindividual variability in its antiplatelet effects [14] should provide a useful paradigm and convince investigators and Journal editors of the need to ban the term ‘resistance’.

Finally, we believe that there is a third area in the aspirin realm where novel studies are needed, i.e. the area where the medical/scientific community has jumped to treatment recommendations supported by extrapolation instead of direct trial evidence. At least two examples are worth mentioning, i.e. diabetes mellitus and ET. Extrapolation was largely based on type-2 diabetes being considered equivalent to established coronary heart disease, and ET potentially benefiting from the same antiplatelet strategy proven effective in polycythemia vera [15]. Both diabetes and ET share the following interesting features: (i) low-dose aspirin is currently being recommended and prescribed in the absence of a single positive randomized trial (in the case of diabetes, two recently published trials [16,17] were negative or inconclusive); (ii) it is biologically plausible that aspirin may be less effective when administered at conventional dose and once daily regimen, because of abnormalities in platelet regeneration; and (iii) there is clearly a need for appropriate pharmacodynamic studies to provide a rational basis for novel clinical trials assessing the efficacy and safety of aspirin in these settings.

Acknowledgments

  1. Top of page
  2. Abstract
  3. The optimal dose
  4. Aspirin ‘resistance’
  5. Balance of benefits and risks
  6. Future directions
  7. Acknowledgments
  8. Disclosure of Conflict of Interests
  9. References

The Authors are supported by the European Commission, EICOSANOX Integrated Project 005033. The expert editorial assistance of Daniela Basilico is gratefully acknowledged.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. The optimal dose
  4. Aspirin ‘resistance’
  5. Balance of benefits and risks
  6. Future directions
  7. Acknowledgments
  8. Disclosure of Conflict of Interests
  9. References

C.P. has received consultant and speaker fees from AstraZeneca, Bayer, Eli Lilly, NicOx, Sanofi-Aventis, Schering-Plough, and Servier. B.R. has received honoraria for lectures from Nycomed, BMS, Bayer.

References

  1. Top of page
  2. Abstract
  3. The optimal dose
  4. Aspirin ‘resistance’
  5. Balance of benefits and risks
  6. Future directions
  7. Acknowledgments
  8. Disclosure of Conflict of Interests
  9. References
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