Aspirin resistance in cardiovascular disease
Authors: Giuseppe Biondi-Zoccai, Marzia Lotrionte
Journal: BMJ (2008)

Aspirin has clear benefits in cardiovascular disease. It reduces total mortality, cardiovascular mortality, and cardiovascular morbidity in people with cardiovascular disease or those at high risk of the disease; it is also cheap, relatively safe, and easy to use.1 So why does aspirin fail to work in some people who take it as prescribed? Research on this clinical “resistance” to aspirin has tried to assess whether the effect on the in vitro activation of platelets depends only on the dose and type of antithrombotic agent given, or whether some people respond poorly (“resist”) to a specific drug, as some people do to specific antibiotics. In the accompanying systematic review, Krasopoulos and colleagues assess whether resistance to aspirin is related to cardiovascular outcomes in people with cardiovascular disease.2

To date, most research has focused on whether aspirin resistance really exists, whether antiplatelet resistance is specific to certain agents or classes of drug,3 and whether resistance carries a worse prognosis. Firstly, no accepted gold standard test to define aspirin resistance is available.4 This and other epidemiological considerations have led some authors to argue that what has been dubbed resistance is just part of normal (Gaussian) variability in pharmacokinetics and pharmacodynamics. Others admit that aspirin resistance exists but are doubtful about its prognostic importance.5 They think that a lack of response to aspirin could just be a proxy marker for more advanced pre-existing disease or less controlled traditional risk factors.

Krasopoulos and colleagues’ review analysed data from 20 studies and 2930 patients and found resistance to aspirin in 28% of people. Resistance was significantly more common in women and those with renal failure and was associated with a statistically and clinically significant increase in the risk of death or adverse cardiovascular events, at least in univariate analysis. However, they found no association between the dose of aspirin or concomitant use of other antiplatelet agents and adverse events. The review has some limitations including use of fixed effect methods and lack of pooled multivariable adjusted estimates. A similar review recently came to the same conclusions, however, confirming the external validity of Krasopoulos and colleagues’ review.6

Despite this work several questions remain. We don’t know whether aspirin resistance is a true abnormal response or whether it reflects normal variability in drug activity. We also aren’t clear whether aspirin resistance has a negative prognostic effect independent of more traditional risk factors, such as diabetes or obesity.5 If aspirin resistance is an abnormal response that results in worse prognosis then what can clinicians do? We suggest that when aspirin resistance is suspected patients should be screened using available tests. Management of patients with aspirin resistance should include a comprehensive appraisal of thrombotic and bleeding risks, the likelihood of non-adherence to treatment, and access to other antiplatelet agents. On the basis of this assessment, several strategies can then be proposed. These include adding another antiplatelet agent (for people at high thrombotic risk and low bleeding risk), substituting aspirin with the more effective clopidogrel (for people at intermediate thrombotic risk and low bleeding risk), increasing the dose of aspirin (for example, to 325 mg/day in people at mildly increased thrombotic risk and low to intermediate bleeding risk), or continuing with the same antiplatelet regimen (for everyone at high bleeding risk).

The problem in finding truly scientific answers to the effectiveness of these strategies lies in the lack of randomised controlled clinical trials. This will probably change, however, as results from trials such as TREND-AR (tirofiban evaluation of surrogate endpoints in prevention of ischaemic complications during percutaneous interventions in patients with coronary disease and aspirin resistance) become available. This trial will randomise patients undergoing percutaneous coronary intervention who have documented aspirin resistance to a combination of clopidogrel, aspirin, heparin, and tirofiban (a potent antiplatelet agent) or clopidogrel, aspirin, and heparin. This trial, among others, will show whether aspirin resistance is just a non-modifiable risk factor (like age or sex) or whether more aggressive antithrombotic regimens are beneficial in patients with aspirin resistance.

Conducting more clinical trials will help fill in the gaps, but another potential reason exists for the interest in aspirin resistance. Drug companies may be keen to downgrade aspirin from its leading role as an effective drug in cardiovascular disease so that they can substitute it with much more expensive but marginally more effective alternatives.