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Aspirin resistancewhen the risks outweigh the benefits

MagazineOctober 2005 (Vol. 16 Issue 7)Aspirin resistancewhen the risks outweigh the benefits

Aspirin's cardioprotective benefits stem from its soothing effect, which calms arterial inflammation

Aspirin's cardioprotective benefits stem from its soothing effect, which calms arterial inflammation. The drug also has antiplatelet properties, making platelets (tiny blood-cell fragments with no nuclei) less sticky and less likely to form clots.

Although aspirin can reduce the risk of secondary events (repeat heart attacks or strokes) by about one-quarter in those with established cardiovascular disease, recent studies expose a worrying aspect of the drug: it doesn't work for everyone. While its pain-relieving potential is universally accepted, its antiplatelet properties are more hit-and-miss - indeed, missing a substantial number of exactly those people who take it religiously in hopes that it will save their lives.

This phenomenon - the occurrence of blood clots that can cause heart attack or stroke despite regular aspirin therapy - is referred to by the medical profession as 'aspirin resistance' (Am Heart J, 2005; 149: 675-80). Given this definition, however, it's no surprise that researchers are now asking whether 'aspirin failure' might not be a more accurate term.

Aspirin resistance appears to be dose-related in some patients and so may be overcome with higher doses. But those are the dosages associated with an increased risk of gastrointestinal bleeding and other established uncomfortable or just plain dangerous side-effects. Yet, for some people, aspirin initially works to thin the blood, but the effect lessens over time.

In other words, they slowly develop a tolerance for aspirin.

A brief history
In the late 1980s, a series of trials showed that the regular use of aspirin reduced the risk of non-fatal stroke and heart attack in cardiovascular patients, as well as lowered the risk of heart attack in men without cardiovascular disease (BMJ, 1988; 296: 320-31; Am J Cardiol 1988; 61: 637-40). This led to the 1989 US Preventive Services Task Force's general recommendation that, from the age of 40 onwards, men who had a propensity for heart disease consider routinely taking low doses of aspirin as a preventative measure.

And more major support of aspirin was yet to come. The 1994 meta-analysis by the Antiplatelet Trialists' Collaboration (ATC) further recommended aspirin use as treatment against stroke, claiming that a few weeks of antiplatelet therapy could halve the risk of deadly blood clots in high-risk patients (BMJ, 1994; 308: 235-46).

However, a critical look at the ATC analysis later that same year exposed major flaws in the studies it covered. In fact, only one of the 16 studies was properly conducted and error-free. Appalling mistakes were rife among the rest of them, including mathematical mistakes and the avoidance of safety issues. In short, there was no evidence to support the widespread use of aspirin to prevent stroke (BMJ, 1994; 309: 1213-5).

Nevertheless, initial enthusiasms die hard. Today, the UK's National Health Service still recommends a daily 75-mg aspirin for secondary prevention of stroke and arterial disease, and a daily 150-mg dose in the event of an acute heart attack (providing there are no contraindications to aspirin such as a history of stomach ulcers or kidney disease).

As for the use of aspirin as primary prevention (reducing the possibility of a first heart attack), the Aspirin Foundation admits that "this has yet to be adequately tested" before ignoring said uncertainties and suggesting that aspirin reduces the risk of non-fatal heart attack by about a third, with a minor (10 per cent) reduction of risk for other cardiovascular problems.

The US Food and Drug Administration's Cardiovascular and Renal Drugs Advisory Panel doesn't support the use of aspirin for the primary prevention of heart attacks. In other words, there is insufficient evidence to suggest that healthy people should routinely ingest aspirin 'just in case'. Yet, despite the lack of solid proof that the drug will work for them, 23 per cent of healthy Americans are voluntarily taking low doses of aspirin regularly in the belief that it will reduce their risk of heart attack and stroke. These individuals tend to be health-conscious and physically active (MMWR, 1997; 46: 498-502).

Aspirin resistance: the evidence
According to the clinical and laboratory evidence, between 5 and 60 per cent of aspirin-takers experience a 'variable' response (or resistance) to aspirin (Pharmacotherapy, 2005; 25: 942-53). Such aspirin resistance, even in a healthy population, translates to a greater than threefold increase in the risk of adverse events (J Am Coll Cardiol, 2003; 41: 961-5).

Even more worrying, a recent study found that, while two months of aspirin treatment markedly reduced the potential for blood clotting, its effect on platelets successively decreased from that point on.

In other words, long-term aspirin treatment is associated with a progressive loss of platelet sensitivity to the drug. The study followed patients for two years, after which blood clots were significantly more likely to occur than they had been at aspirin's peak-performance period of two months (J Am Coll Cardiol, 2004; 43: 979-84).

This may explain why a significant proportion (approximately one in eight) of high-risk patients will suffer 'breakthrough' events within two years, despite regular aspirin intake (Indian Heart J, 2003; 55: 217-22).

It also makes sense of a study that found that angina patients previously on long-term aspirin treatment were 20 per cent more likely to have a recurrent event within six months compared with patients not previously on aspirin therapy (Am J Cardiol, 1999; 83: 1147-51).

To make matters worse, current smokers and patients with diabetes, previous stroke, heart failure, high blood cholesterol or coronary artery disease - all those who are most at risk of cardiovascular events - are the ones who are more likely to develop aspirin resistance (Rev Med Chil, 2005; 133: 409-17; Thromb J, 2004; 2: 1; Acta Diabetol, 2005; 42: 99-103; Am J Health Syst Pharm, 2005; 62: 1398-405).

Disputed dosages
Aspirin resistance is more likely to occur when patients with coronary artery disease take less than 100 mg/day, which produces fewer side-effects, compared with 150 mg/ day or 300 mg/day (Am J Med, 2005; 118: 723-7). An earlier study found that while 25 per cent of cardiovascular patients were initially resistant to aspirin even at the relatively high dose of 325 mg/day, that percentage dropped to just 8 per cent when the dose was increased to 1300 mg/day (Stroke, 1994; 25: 2331-6). These data appear to suggest that a high dose is more effective.

If only it were that simple. A meta-analysis found that high-dose aspirin (500-1500 mg/day) was no more effective than low doses (75-150 mg/day) in reducing vascular events in high-risk patients (J Am Coll Cardiol, 2003; 41: 966-8). This could mean that aspirin doesn't exert its antithrombotic effects as an antiplatelet inhibitor, but through some other mechanism.

It could also suggest that researchers and clinicians still aren't sure how aspirin really works, which is why aspirin resistance is a particularly frustrating phenomenon.

But it is most likely to mean that high-risk patients - who are also probably those who have been taking a long-term course of aspirin and have developed a tolerance to it - simply aren't responding to it anymore, no matter how much they take.

And what about those healthy people who are taking aspirin for vague preventative purposes? A recent study of healthy volunteers found that their platelets did not respond well to low-dose aspirin; to be effective, a dose of at least 500 mg/day is required (Circulation, 1997; 95: 63-8).

But, as we already know, high doses of aspirin are linked to a higher incidence of side-effects such as gastrointestinal and cerebrovascular bleeding (Circulation, 2002; 105: 1650-5; Hellenic J Cardiol, 2004; 45: 1-5). Clearly, the potential benefits of aspirin need to be weighed against these risks and the risks of the known side-effects of any alternative drugs.

The clopidogrel connection
One such alternative, clopidogrel (Plavix), is a more expensive antiplatelet agent widely prescribed for atherothrombotic disease. It is often used with aspirin to maximise antiplatelet benefit. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial showed that heart patients treated with both aspirin and clopidogrel within 24 hours had a 20 per cent relative-risk reduction in vascular events compared with aspirin alone (N Engl J Med, 2001; 345: 494-502). However, there was also an increased risk of major bleeding with clopidogrel.

But, in a randomised blinded trial of clopidogrel vs aspirin in patients at risk of ischaemia (CAPRIE), clopidogrel proved more effective in reducing cardiovascular risk than aspirin (Lancet, 1996; 348: 1329-39). So, for patients who respond poorly to aspirin, clopidogrel may yet be a better option as it works in a slightly different way.

Nevertheless, as with aspirin, clopidogrel resistance has been reported (Thromb Haemost, 2003; 89: 783-7; Am J Cardiol, 2003; 91: 1123-5). Looking at both drugs together, resistance is seen in more than half the patients chronically taking either aspirin or clopidogrel (Curr Cardiol Rep, 2005; 7: 242-8).

Physicians are now in a bind. Faced with a high-risk and potentially aspirin-resistant patient, they can either prescribe the more expensive treatment in addition to aspirin (increasing the risk of serious side-effects), or they can remove aspirin from the cocktail and rely on clopidogrel - and risk resistance to it instead, and still have the possibility of bleeding.

And should both drugs be offered to all patients, or should clopidogrel or the other, new antiplatelet agents be used only in cases of apparent aspirin-resistance? Given that most cardiovascular patients are already on potentially interacting medications such as ACE inhibitors and statins, it seems imprudent to prescribe anything remotely unnecessary.

To test or not to test?
Lab tests such as the platelet-function analyser PFA-100(R) use blood samples to measure platelet reaction on exposure to aspirin, and may be useful for identifying aspirin resistance in some patients (Thromb Haemost, 2000; 83: 316-21). AspirinWorks is a test that measures levels of thromboxane in the urine - low levels mean the aspirin is working.

But medical opinion is divided as to whether aspirin testing should be routine for high-risk patients. Those against the idea believe that more facts on the mechanism of aspirin resistance are needed. They also question the validity of test results.

Nevertheless, more and more physicians in the US have begun to routinely test their patients. Whether evidence is conclusive or not at this time, they say, it's reasonable to alter therapy rather than to continue to prescribe a drug that testing shows may well be ineffective for the given patient. Add to that the unnecessary complications of possible gastrointestinal bleeding, tinnitus, a worsening of asthma and the host of other, well-known complaints with chronic aspirin ingestion, and the benefits of considering another method of treatment do add up.

What is clear - at least, what clinicians appear to agree on - is that aspirin resistance is a poorly defined term. Doctors question the clinical data on which tests recently marketed in the US are based, and await the development of a sensitive and specific assay that can reliably predict treatment failure (Pharmacotherapy, 2005; 25: 942-53; BMJ, 2004; 328: 477-9). Proposed causes of failure include anything from poor patient compliance and the use of contraindicated medications to an increased turnover of platelets and poor aspirin uptake.

Whether resistance means the inability of aspirin to protect against arterial thrombosis, the failure of aspirin to affect platelets and reduce clotting in a test-tube, or a specific urinary concentration of a metabolite called thromboxane is anyone's guess. What we do know is that it's a documented problem - which is more than many physicians (not to mention the aspirin suppliers, protecting their cash cow) want us to know.

Kim Wallace


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