It's the inexpensive and readily available magic bullet that can protect us against cardiovascular disease, mankind's greatest killer. The humble aspirin can, according to its proponents, reduce blood pressure and help thin the blood, so lowering the risk of stroke and heart attack-two functions that today dwarf its original purpose as a painkiller, an anti-inflammatory and antipyretic (fever-reducer).
Best of all, it appears to be a relatively benign drug. The Ameri-can Association of Poison Control Centers receives reports of just 59 aspirin deaths in the US each year, while researchers put the mortal-ity rate for all painkilling, non-steroidal, anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen and naproxen at around 7600 deaths a year (Scand J Rheum Suppl, 1992; 92: 21-4).
Either way, doctors argue that these figures represent an entirely acceptable risk compared with the many thousands more who might otherwise have died because of heart disease.
But scientists are now discov-ering that we have all been dramatically-and catastrophically -misled by the assurances of the medical community. Far from being benign, aspirin may be a major killer in our society, and one thatis never suspected.
The new claim centres on the drug's well-documented side-effect of causing serious-and, in some cases, fatal-gastrointestinal (GI) bleeding. But researchers in a separate study have discovered a new, and worrying, side-effect of aspirin-it may be a major cause of stroke among the elderly. Because of its widespread use, researchers warn that these little pills may soon overtake hypertension (high blood pressure) as the major cause of stroke.
What studies now tell us
In the first of the new studies, researchers reckoned that the drug is killing 20,000 Americans-and sending another 100,000 to hospital-every year just becauseof GI problems. Astonishingly, each of these deaths and reactions is slipping under the radar, and is not being associated with aspirin at all.
Researchers at the Eastern Virginia Medical School made their alarming discovery when they interviewed patients at a clinic that specializes in GI problems. They found that one in five patients was taking aspirin or some other painkilling NSAID, but the fact wasn't being reported to the medi-cal staff because it wasn't regarded as significant.
"This reflects a common mis-perception that these medications are insignificant or benign when actually their chronic use, partic-ularly among the elderly and those with conditions such as arthritis, is linked to serious and potentially fatal GI injury and bleeding," said Dr David Johnson, one of the Vir-ginia researchers.
If the researchers' death and injury rates for the US is correct, this could mean that the worldwide aspirin and other NSAID death toll is 100,000 individuals every year. What's more, a further 500,000 of us will need hospital care to treat a serious reaction to the drug, such as the result of a GI reaction (Proceedings of the Annual Scientific Meeting of the American College of Gastroenterology, 15 October 2007). Currently, none of these deaths is even recorded as an aspirin fatality.
Equally worrying is the drug's effect among the over-75s. Far from protecting them against stroke, it appears to be causing just such an attack that is either fatal or results in disability. Researchers at Oxford University have discovered that
the drug has caused a sevenfold increase in intracerebral haemor-rhagic stroke-bleeding within the brain-during the past 25 years among groups of elderly patients who participated in their trial.
Research-team leader Professor Peter Rothwell says that aspirin may soon replace high blood pressure as the leading cause of intracerebral haemorrhagic stroke, especially among the over-75s.
"There are elderly people who take aspirin as a lifestyle choice," he says, "and, in that situation, the trials have shown there's no bene-fit. And what our study suggests is that, particularly in the very elderly, the risks of aspirin out-weigh the benefits."
In Rothwell's study, researchers assessed the records of stroke victims between 1981 and 1985, and again between 2002 and 2006. While the overall rate of stroke caused by high blood pressure had dropped by 65 per cent between those two periods, the rate among the over-75s remained the same, mainly because there had been an increase in the number of strokes among patients taking blood-thinners such as aspirin.
The team discovered that the use of these drugs had increased dramatically and especially among healthy people who were taking the drugs as a preventative. From 1981 to 1985, only 4 per cent of patients were taking a blood-thinner, but this had risen to 40 per cent between 2002 and 2006 (Lancet Neurology, 2007; 6: 487-93).
In fact, the true dangers of aspirin have been known for some time, although no one has been prepared to do anything about it. Scientists from the West Midlands Regional Health Authority in Birmingham were among the first to raise the warning flag 12 years ago, when they did an investigation into the reasons why people were in hospital for treatment of bleeding peptic ulcer.
At that time, they discovered that 12.8 per cent of the 1121 patients being investigated were regular users of aspirin, which they defined as five days a week for at least a month. When they compared these patients against other patients with the same prob-lem, but who were not regularly taking aspirin, it was evident that taking the NSAID had increased the risk of hospitalization for bleeding peptic ulcer by 2.3 times at a low dose of just 75 mg, and by up to 3.9 times at the more standard dose of 300 mg (BMJ, 1995; 310: 827-30). The 300-mg dose is the recommended level for just-in-case, or prophylactic, use against heart disease.
These researchers didn't track the progress of patients after identifying their cause of hospital-ization, but one group of scientists did-and came up with a horrifying picture. Of those who were being treated in hospital for serious upper gastrointestinal bleeding or perforation, 10 per cent had died.
Who are most at risk?
This alarming scenario was derived from an analysis of 12 studies published between 1980 and 2000. Those who were especially at risk were older individuals, and there were around twice as many men as women who ended up in hospital
(J Clin Epidemiol, 2002; 55: 1057-63).
So, as well as age and gender, people who take several NSAIDs in combination also increase their risk of having a serious GI reaction. In a separate study, researchers who examined patients' records from databases in the UK and Spain found that 60 per cent of those who suffered a GI reaction from an NSAID were aged over 60, 13 per cent were using several NSAIDs in combination, and 6 per cent had a recent history of peptic ulcers, even though patients with pre-existing GI problems should not be taking any sort of NSAID in the first place (BMC Medicine, 2006; 4: 22).
But perhaps the most lethal drug combination is an NSAID with an SSRI (selective serotonin reuptake inhibitor) type of antidepressant such as Prozac, Zoloft or Paxil. In fact, this is a common drug cock-tail, especially among arthritis sufferers, who are often given an NSAID to ease their joint pain and inflammation, and an SSRI to ease their mild depression.
When these two drugs are taken concomitantly, the risk of upper GI haemorrhage increases by 6.3 times. Translated into everyday usage, a patient has to take the combination just 82 times before suffering a serious gastrointestinal adverse reaction. Such an event would occur less than three months into the treatment, assuming the combination is taken daily.
Researchers from the University of East Anglia made this discovery when they carried out a meta-analysis of four trials involving a total of 153,000 patients who were taking either an SSRI or an NSAID, or a combination of the two types of drug. Patients who took just the SSRI increased their risk of a GI reaction 2.4 times, and those taking just an NSAID had a 3.2-times greater risk (Aliment Pharmacol Ther, 5 October 2007; doi: 10.1111/j.1365-2036.2007.03541).
Lead researcher Dr Yoon K. Loke commented: "Before I did this study, I didn't worry at all when I saw patients who were on com-binations of SSRIs and NSAIDs. Now that I have seen the fairly substantial excess risk, physicians should review the patients' charts-do they need to be on these drugs at all, or are there safer alternatives?"
Gastrointestinal problems with aspirin have been known for a long time-even if the actual severity and extent have only recently been revealed-and manufacturers have tried to reduce the risks by either producing a version that is enteric-coated, which allows the tablet to transit through the stomach to the small intestine before releasing the medicine, or buffered, where the standard pill is coated with a sub-stance that neutralizes stomach acid.
But again, far from reducing the GI risk, these coatings appear to increase it. Researchers from the Boston University School of Medi-cine interviewed 550 hospital patients who had major upper gastrointestinal bleeding about their aspirin use. To their surprise, they found that those who had regularly taken buffered aspirin were at a slightly greater risk of developing GI problems than were those taking regular aspirin tablets. At doses greater than 325 mg, patients taking the buffered tablets were seven times more likely to develop GI problems whereas the risk was increased nearly sixfold with the standard pills (Lancet, 1996; 348: 1413-6).
Aspirin: still a wonder drug?
Extraordinarily, the popular use of aspirin seems to be immune toany bad news. This may be because aspirin is still perceived as being a 'wonder drug'. Every year, it's estimated that around 3500 studies are carried out on the drug, and researchers seem to consistently come up with new health problems that they believe it can solve. It's been claimed to fight cataracts (Arch Ophthalmol, 1992; 110: 339-42),and cancers of the prostate, colon, pancreas, upper GI tract, and lung-claims that usually no one is able to replicate and so are, eventually, forgotten.
This is, of course, in addition to its more traditional, and accepted, uses as an antipyretic to reduce fever in cases of rheumatic fever, as an anti-inflammatory in cases of rheumatoid arthritis and osteo-arthritis, and as a painkiller for minor aches and pains such as headache.
But if the risks of regularly taking aspirin outweigh its benefits among healthy over-75s, as suggest-ed by Oxford's Professor Rothwell, then should healthy individuals of any age be taking it?
Not according to Charles H. Hennekens, former chief of preven-tive medicine at Brigham and Women's Hospital in Boston, and one of aspirin's main advocates. Yet, even he believes it is wrong for any healthy individual to take aspirin as a preventative as the risks are simply too high.
"A 30-year-old woman's risk of a heart attack is typically very small, and remains so even over the next 30 years. Aspirin would give her no benefit and it could cause gastro-intestinal effects or dangerous bleeding," he says in a Food and Drug Administration (FDA) report.
Children aged under 12 should also no longer be given aspirin because of the very real danger of Reye's syndrome, a rare, often fatal, disorder primarily seen in children recovering from a viral illness and associated with aspirin use (BMJ, 2002; 325: 988).
If the healthy should not be taking aspirin, this suggests that nearly 40 per cent of daily aspirin use is inappropriate, and may even be endangering thousands of lives without any realistic benefits.
Nevertheless, it should be part of the daily health regime of any-one who has a heart problem, says the American Heart Foundation. It estimates that between 5000 to 10,000 of the 900,000 lives lost each year to cardiovascular disease in the US alone could have been prevented had the patient taken a daily aspirin. It points to research that suggests that aspirin can help to prolong the lives of people who have suffered a stroke or heart attack, or recurring blockages following heart bypass surgery or angioplasty to clear obstructed arteries.
But these positive claims have to be countered with the more recent findings that the drug could be kill-ing 20,000 Americans every year because of GI complications alone, a figure that may well increase if stroke victims are also included.
But no drug is a substitute for a sensible lifestyle. A healthy diet that is rich in vegetables and fruit, moderate exercise, and stress- and cigarette-free living can do more for the healthy individual and the recovering patient alike.
As the FDA's Debra Bowen says: "Physicians really need to look at aspirin in the context of complete care, as part of a whole treatment plan for people at risk of heart attack or stroke."
It's a view shared by Dr Peter Coleman, deputy director of res-earch for the Stroke Association in the UK. He says: "If you are healthy and have a low risk of heart disease or stroke, the increased risk from side-effects of aspirin are likely to outweigh the benefits of preventing stroke."
Aspirin is as close as medicine has ever come to producing a magic bullet-and one that appears to be Teflon-coated, too. Neverthe-less, given these latest discoveries, it's an ideal that is apparently as far away as ever.
The story of aspirin
Aspirin holds an unusual place in trademark law. As 'Aspirin' with a capital 'A', it is a protected brand, owned by Bayer, the German pharmaceutical giant.
As 'aspirin', it is a generic drug that can be used in countries where Aspirin is not trademark-protected. Around 50 other over-the-counter preparations contain aspirin, using either the name or ASA, an abbreviation that stands for Aspirin's generic name, acetylsalicylic acid.
Aspirin was the very first drug in the family of NSAIDs (non-steroidal, anti-inflammatory drugs) when Bayer began marketing it in 1899, along with another of the company's discoveries, heroin. Its principal ingredient is salicylic acid, derived from the bark of the willow tree and from the herb meadowsweet. It was recognized by Hippocrates as a pain-reliever and an antipyretic (fever-reducer) as long ago as in the 5th century bc.
Chemists at Bayer were successful in synthesizing salicylic acid with the common chemical acetic anhydride, so giving Aspirin its generic name.
Despite its widespread use and popularity, no one understood how the drug worked until 1971, when the British pharmacologist John Vane found that aspirin suppresses the production of prostaglandins and thromboxanes, hormones that regulate many physiol-ogical functions.
Today, we globally consume around 35,000 tons of aspirin every year-amounting to around 100 billion tablets-a figure that is increasing annually by 15 per cent. Aspirin continues to be viewed as a benign painkiller, which has helped to fuel its growing use at a time when bad news and scares have hounded some of the other NSAIDs and COX-2 drugs.
Most recently, the COX-2 painkiller Vioxx was withdrawn from the market after it was found to cause heart problems-some fatal. It was the subject of the largest civil lawsuit in history until its manufacturer Merck settled with a $4.85bn payout.
Aspirin has been dogged by its own fair share of side-effects. The most common are stomach bleeding and other GI problems, but added to that are stroke, anaemia, ulcers, liver damage, hives, wheezing, tinnitus, chronic catarrh, headache, confusion and hypotension (low blood pressure) followed by collapse. Asthmatics have also died from a severe attack after having taken aspirin.
Is it truly a heart helper?
Aspirin's popularity today is more to do with its ability to protect us from cardiovascular disease (CVD) than as a painkiller, for which it has been superseded by newer kids on the block such as ibuprofen.
Around 37 per cent of the 100 billion aspirin pills swallowed every year are taken as a preventative against heart disease and stroke, while 23 per cent of users are arthritis sufferers who take it for its anti-inflammatory qualities. Only 14 per cent of users take it to relieve a headache.
Its principal role as an anti-inflammatory and antipyretic began to change when Dr L.L. Craven, a GP working in California, discovered that it was providing benefit to his heart patients (Mississippi Valley Med J, 1953; 75: 38-44).
More recent trials have confirmed its role as a preventative agent, and particularly for heart patients. In 1998, the US drugs regulator, the Food and Drug Administration (FDA), widened the scope of aspirin to encompass its new role, especially among those who had had a heart attack, stroke, angina, or bypass surgery or angioplasty.
Since then, two meta-analyses have concluded that aspirin can reduce the risk of cardiovascular disease by 13 per cent (Arch Intern Med, 2000; 160: 3123-7), and heart attack by as much as 32 per cent (Heart, 2001; 85: 265-71).
Despite these glowing recommendations, however, many groups remain cautious and recommend that healthy people not use aspirin as a prophylactic-just-in-case. The US Preventive Service Task Force is still not convinced and, despite the meta-analyses, says the data are insufficient to make any categorical pronouncement (Ann Intern Med, 2002; 136: 157-60). The European Society of Cardiology suggests that those at high risk of heart disease should take aspirin only at a low daily dose of 75 mg.
Similar cautious voices have been raised concerning aspirin's ability to prevent stroke, despite the seemingly impressive research. The Antiplatelet Trialists' Collaboration (ATC) prepared a series of landmark trials that appeared to establish aspirin as an important agent for treating stroke.
Yet, within a year, its findings were being questioned. The Thrombosis Research Institute analyzed the third arm of the ATC trial, which focused on the efficacy of aspirin in reducing venous thrombosis and pulmonary embolism after surgery. The Institute declared that some of the ATC's conclusions were not justified, and that several of the studies included in the meta-analyses weren't of a high-enough standard (BMJ, 1994; 308: 1213-7).
Worse, the ATC researchers had also played down the issue of side-effects such as internal bleeding. Without them, said the Institute, the true risk-benefit ratios couldn't be worked out.
In the face of these criticisms, the ATC researchers moved away from their earlier effusive position and instead suggested that aspirin was not the com-plete solution, but should be seen as part of a range of measures.
The ATC studies were an interesting object lesson in how the myth of the healing powers of aspirin always manages to outpace the actual studies on which it has been founded. Nevertheless, despite the legend, there is only a handful of research to support the theory that aspirin can prevent heart disease and stroke. Even used as a preventative by heart patients, the evidence is thin on the ground.
The editorial team of a prestigious peer-reviewed journal once stated that "aspirin seems as effective as any other single agent or combination of agents" (BMJ, 1994; 308: 71-2), which is saying far less than aspirin's advocates believe.