The efficacy of aspirin in secondary prevention of cardiovascular disease is well understood but its position in primary prevention of cardiovascular events is less clear.
Tailoring treatment
Insufficient pharmacological inhibition of platelet COX-derived thromboxane formation is often perceived as lack of effectiveness of antiplatelet therapy and is a major concern. Multiple factors, including lack of compliance, may contribute to this issue and true resistance is rare (1–2%). The assumption that a single dose is suitable for all patients is based on retrospective data and this assumption is now being challenged. For clopidogrel, even a 600 mg loading dose appears to be ineffective in some patients undergoing stent implantation but antiplatelet efficacy is not checked adequately before the procedure. It is estimated that 19% of the variation in response to clopidogrel is associated with variants in the 2C19 gene, for which 30% of Caucasians are heterozygous; it may be possible to genotype patients to identify those at risk.
Development of accurate but simple near-patient testing for platelet function that can be linked to patient outcomes is needed. This testing will identify patients who have not responded to antiplatelet therapy. Some current tests, such as VerifyNow, are convenient to use and produce a simple result; although popular with clinicians, it is difficult to understand what it means and there is marked interpatient and intrapatient variability. As understanding develops, platelet function testing may become as routine as measuring blood pressure. It is hoped that this will help clinicians tailor drug dosage to individual need and responsiveness and identify individuals who may require and benefit from more expensive agents.
Bleeding
The increased risk of bleeding associated with dual therapy with aspirin plus clopidogrel compared with monotherapy may possibly be attributable mainly to clopidogrel, and in particular to a high-dose clopidogrel regimen (600 mg), though this only appears to be significant in patients at high risk (such as acute coronary syndrome [ACS] patients undergoing percutaneous coronary intervention [PCI]). Although overall the incremental increase in risk associated with dual therapy compared with monotherapy is less than the incremental gain in benefit from the greater antithrombotic effect, treatment needs to be tailored to the individual patient and trial results are helpful in this respect. It is likely that such a high dose of clopidogrel is prescribed only because platelet function tests are uninformative.
Clinicians are rightly concerned about the risk of bleeding due to antiplatelet therapy but the occurrence of a stroke due to non-treatment is a more serious risk. Conversely, it is unknown how often minor bleeding events such as epistaxis or bleeding haemorrhoids cause patients to stop taking aspirin. More work is needed on presentation and interpretation of this risk. Further, it is not known whether the severity of gastrointestinal bleeding associated with antiplatelet agents differs from bleeding due to other causes. Older trials should be reanalysed to determine the severity of this end point and the findings should be considered in the design of prospective trials to clarify the balance of risk. The severity of events could be measured on a simple ordinal scale for morbidity and mortality.
New primary prevention trials of aspirin
The Critical Leg Ischaemia Prevention Study (CLIPS) showed that primary prevention with aspirin significantly reduced vascular events in patients with peripheral arterial disease1 but was not adequately recognised. Trials of low-dose aspirin now underway should provide new evidence about its role in primary prevention in the next 5–7 years. In the Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) study (www.arrive-study.com), efficacy and safety end points will be adjudicated. The ASCEND trial (A Study of Cardiovascular Events iN Diabetes), based in Oxford, (www.ctsu.ox.ac.uk/ascend) is a randomised trial that should provide the first reliable evidence about the effects of aspirin and of omega-3 fatty acids in diabetes. ASCEND aims to recruit at least 10,000 people with diabetes (either type 1 or type 2) who do not have known vascular disease.
In addition, ASPREE (ASPirin in Reducing Events in the Elderly; http://www.med.monash.edu.au/epidemiology/cardiores/aspree) started in Australia in 2009 and will start in the US in 2010. It is a large-scale, double-blind primary prevention trial of aspirin versus placebo over a five-year treatment period conducted in 19,000 healthy elderly people aged 70 years and over. The purpose of the trial is to determine whether low-dose aspirin (100 mg/day) will extend the duration of healthy life in an ageing population. The study will examine whether the potential benefits of aspirin (particularly the prevention of heart disease, stroke and dementia) outweigh the risks of severe bleeding in this age group.
JPPP (Japanese Primary Prevention Project with aspirin in elderly patients with one or more risk factors for vascular events) is a four to five year nationwide, centrally randomised controlled trial evaluating the ability of low-dose, enteric-coated aspirin to prevent CVD events in elderly Japanese patients with hypertension, hyperlipidaemia and/or diabetes, comparing aspirin with placebo in approximately 10,000 patients aged 60-85 years. Primary end points include a composite of CVD death, non-fatal stroke and non-fatal MI. Additional study end points to be evaluated include non-CVD deaths, angina pectoris, transient ischaemic attacks, surgery or intervention for arteriosclerotic disease, and bleeding complications.
In summary, the results obtained in studies and meta-analyses are quantitatively in line with the beneficial results seen in secondary prevention, strongly suggesting that aspirin reduces the incidence of a first MI (and other vascular end points) in asymptomatic patients with vascular risk factors. In order to identify the appropriate target population in which the benefits of aspirin clearly outweigh the risks, it is important to take into consideration the overall cardiovascular risk profile of each individual patient.
Steve Chaplin
Reference
- Critical Leg Ischaemia Prevention Study (CLIPS) Group. Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double-blind trial. J Intern Med 2007;261:276–84.
