Editorials

Aspirin resistance

BMJ 2004; 328 doi: http://dx.doi.org/10.1136/bmj.328.7438.477 (Published 26 February 2004) Cite this as: BMJ 2004;328:477
  1. Graeme J Hankey, consultant neurologist (gjhankey{at}cyllene.uwa.edu.au),
  2. John W Eikelboom, consultant haematologist
  1. Stroke Unit, Department of Neurology, Royal Perth Hospital, Box X2213 GPO, Perth, WA 6001, Australia
  2. Department of Haematology, Royal Perth Hospital

    May be a cause of recurrent ischaemic vascular events in patients taking aspirin

    Aspirin reduces the odds of serious atherothrombotic vascular events and death in a broad category of high risk patients by about one quarter.1 The primary antithrombotic mechanism is believed to be inhibition of the biosynthesis of thromboxane (and thus platelet activation) by inactivation of platelet cyclo-oxygenase-1. However, aspirin is not that effective. It still fails to prevent most (at least 75%) serious vascular events in patients with symptomatic atherothrombosis.1 Recurrent vascular events in patients taking aspirin (“aspirin treatment failures”) have many possible causes (box), and aspirin resistance has emerged as an additional contender.2 3

    But what is aspirin resistance? Aspirin resistance has been used to describe several different phenomena. One is the inability of aspirin to protect patients from ischaemic vascular events. This has also been called clinical aspirin resistance.4 However, this definition is non-specific and could apply to any of the conditions listed in the box. Furthermore, it is not realistic to expect that all vascular complications can be prevented by any single preventive strategy.5 Aspirin resistance has also been used to describe an inability of aspirin to produce an anticipated effect on one or more tests of platelet function, such as inhibiting biosynthesis of thromboxane,6 inhibiting platelet aggregation,7 and causing a prolongation of the bleeding time.5 8 This has been called biochemical aspirin resistance.4 However, the precise qualitative and quantitative abnormalities of platelet function which define biochemical aspirin resistance have not been established, let alone their clinical relevance. As shown in the table, there are several different laboratory tests of platelet function which are being used to diagnose “biochemical” aspirin resistance, and each has its own limitations.

    Table 1

    Laboratory tests used to measure the antiplatelet effects of aspirin

    View this table:

    For a laboratory measure of biochemical aspirin resistance to have clinical utility it must be associated independently and consistently with the occurrence of recurrent vascular events in patients taking aspirin; it must be standardised and valid; and clinical management should be altered on the basis of the results of testing—for example, it should be shown in randomised controlled trials that reversing the laboratory abnormality (with treatment) is followed by a reduction in the incidence of recurrent vascular events while taking aspirin. Finally, the overall benefits of testing should outweigh any adverse consequences and costs.9

    Two recent studies meet the first criterion, but no study meets the other three criteria. The first study showed an independent and significant association between increasing baseline urinary concentrations of 11-dehydrothromboxane B2 (a marker of in vivo thromboxane generation) and an increasing risk of future myocardial infarction or cardiovascular death in patients at high vascular risk who were treated with aspirin.6 The second study showed an independent and significant association between the failure of aspirin to suppress agonist induced platelet aggregation and an increasing risk of serious vascular events in 326 patients with coronary or cerebral vascular disease who were treated with aspirin (hazard ratio 4.1, 95% confidence interval 1.4 to 12.1).7 In this study platelet aggregation was measured by optical platelet aggregometry. These data also show that up to 20% of future serious vascular events in high risk vascular patients may be attributable to a failure of aspirin to suppress thromboxane production or platelet aggregation.6 7

    The therapeutic implications of a valid and reliable screening test for aspirin resistance, coupled with an effective treatment, are exciting. However, before aspirin resistance can be accepted as a valid clinical entity worthy of screening and treatment, the other criteria mentioned above must be met. The first step is to develop a standardised definition and test of aspirin resistance. An appropriate definition of aspirin resistance may be: the lack of anticipated response to a therapeutic dose of aspirin (75-150 mg per day for at least five days in a compliant patient) that can be demonstrated by a specific, valid, and reliable laboratory measure of the antiplatelet effects of aspirin and which correlates significantly, independently, and consistently with an increased incidence of atherothrombotic vascular events. The definition may be refined in the future to include proven genetic determinants (for example, platelet polymorphisms), which mediate aspirin resistance and risk of ischaemic events. Further studies are required to externally validate the promise of urinary 11-dehydrothromboxane B2 and optical platelet aggregometry as laboratory measures of “clinical” aspirin resistance.

    Possible causes of recurrent ischaemic vascular events among patients taking aspirin

    Non-atherothrombotic causes of vascular events

    • Embolism from the heart (red, fibrin thrombi; vegetations; calcium; tumour; prostheses)

    • Arteritis

    Reduced bioavailability of aspirin

    • Inadequate intake of aspirin (poor compliance)

    • Inadequate dose of aspirin

    • Concurrent intake of certain non steroidal anti-inflammatory drugs (for example ibuprofen, indomethacin), possibly preventing the access of aspirin to cyclo-oxygenase-1 binding site

    Alternative pathways of platelet activation

    • Platelet activation by pathways that are not blocked by aspirin (for example, red cell induced platelet activation: stimulation of collagen, adenosine diphosphate, epinephrine, and thrombin receptors on platelets)

    • Increased platelet sensitivity to collagen and adenosine diphosphate

    • Biosynthesis of thromboxane by pathways that are not blocked by aspirin (for example, by cyclo-oxygenase-2 in monocytes and macrophages, and vascular endothelial cells)

    Increased turnover of platelets

    • Increased production of platelets by the bone marrow in response to stress (for example, after coronary artery bypass surgery), introducing into blood stream newly formed platelets unexposed to aspirin during the 24 hour dose interval (aspirin is given once daily and has only a 20 minute half life)

    Genetic polymorphisms

    • Polymorphisms involving platelet glycoprotein Ia/IIa, Ib/V/IX, and IIb/IIIa receptors, and collagen and von Willebrand factor receptors

    • Polymorphisms of cyclo-oxygenase-1, cyclo-oxygenase-2, thromboxane A2-synthase, or other arachidonate metabolism enzymes

    • Factor XIII Val34Leu polymorphism, leading to variable inhibition of factor XIII activation by low dose aspirin

    While awaiting the development of a reliable test and effective treatment for aspirin resistance, the most efficient strategy for clinicians to prevent aspirin failure is to make sure that the index event was atherothrombotic in origin, use an appropriate dose of aspirin (75-150 mg daily), maintain a high level of compliance, and avoid combining aspirin with drugs such as ibuprofen that may reduce its effectiveness for the prevention of atherothrombotic vascular events.10 11

    Footnotes

    • Competing interests GJH and JWE have received honorariums for speaking at scientific meetings from Bristol-Myer Squibb and Sanofi-Synthelabo (manufacturer of clopidogrel). GJH has also received honorariums from Boehringer-Ingelheim (manufacturer of dypridamole) and Bayer (manufacturer of aspirin).

    References