At last weekend’s European Society of Cardiology conference in Madrid, a quiet funeral bell tolled for aspirin. The drug has already been largely dropped as a painkiller, on the basis of having more side effects than paracetamol. Most often now it’s taken to prevent a heart attack. Now, a new study, published in the Lancet and presented in Spain, shows another drug, clopidogrel, does it better.
The difference is small, but medicine, like life, is often about finessing small differences. They sum together, and aspirin is part of why living a long, healthy life has become the norm when it used to be unusual good luck.
The history of aspirin teaches that small differences save lives
Reverend Edward Stone, walking near Chipping Norton in 1757, and for reasons still delightfully unclear, chewed willow bark. ‘I accidentally tasted it,’ he said. The bitterness reminded Stone of cinchona bark – quinine – whose tart snap still provides the tonic for gin. Superstition held that God placed cures where He placed diseases, and willow thrived in the same damp soils as malaria, then endemic, so Stone began dosing his patients.
Fevers responded well, he told the Royal Society, reporting that willow bark had been successful in every case tried, except in those whose disease was fatal. Cinchona was expensive and willow was cheap, and it occurred neither to Stone nor his colleagues that abolishing a fever might be different from curing a disease. Willow, which did not work for malaria, partly replaced cinchona, which did. This was deemed progress.
A century later, under interrogation from 19th-century German chemists, willow yielded its secret. Johann Buchner called the active ingredient salicin, from the tree’s genus name Salix. Salicin worked but was harsh on the stomach. Decades later, at Bayer, Arthur Eichengrün found acetylsalicylic acid gentler but as effective. He’d started with salicin extracted not only from willow but also Spirea, meadowsweet. Eichengrün, whose role Bayer later effaced in favour of a non-Jewish colleague, jiggled the letters and came up with a tradename: Aspirin. During the Great War, anti-German sentiment – dachshunds were stoned in London streets – meant the trademark was ignored, and the drug never regained its capital letter.
After the war came influenza, for which aspirin was used hugely. The drug helped with the fever, but whether it helped people survive – or killed them, because fevers are the body’s way of fighting off an infection – is not knowable. The drug’s benefits were assumed and its harms unmeasured.
Bayer morphed into I.G. Farben, who funded the Nazis both bureaucratically and financially. Their rewards included their own manufacturing plant at Auschwitz, complete with slave labour and subjects for forced human experiments. Fritz ter Meer, responsible for the plant, defended himself at Nuremberg on the grounds that victims of the medical experiments were not subjected to unacceptable suffering since they were going to die anyway. He was jailed in 1948 for mass murder and slavery – then released in 1950, for good behaviour. Bayer appointed him chairman.
Post-war, heart disease loomed larger. In a crucial way, it was a good problem to have. Throughout history, infections frequently plucked young people to the grave. Now nutrition, housing, sanitation – and, post-war, penicillin – made survival into middle age normal. Heart attacks, known to be caused by clots and to be chiefly a danger of later life, grew in importance.
Laurence Craven, an American GP, noticed aspirin made people bleed more. To double check, he swallowed it until his nose bled – convinced that was warrant enough to tell his patients to take it to prevent heart attacks. Astute, industrious, and well-intentioned, Craven used aspirin on the basis of hopeful guesswork, not science, just as doctors with his laudable attributes and lack of scientific method had previously used leeches. This time his hunch was partly right, but without a proper trial he could prove that neither to himself nor others. He died in 1957 – of a heart attack.
Those proper trials were eventually done, but even when they included up to 2,000 people, their results were unclear. By 1980, statisticians were learning how to combine the results from multiple studies for improved clarity, but few doctors or regulators understood their methods, and America’s Food and Drug Administration (FDA) refused to approve aspirin for use in heart disease. They refused again in 1983 – not because the data were unclear but because they didn’t understand. People died who could and should have lived.
In 1984, an Oxford statistician, Richard Peto, changed the FDA’s mind. ‘You will hear some doctor saying,’ he said to them, ‘well, if it doesn’t show up in a trial with a couple of hundred patients then it can’t be worth bothering with. This is not medical wisdom but statistical unwisdom.’ His point was that minor differences, undetectable without large trials, remain meaningful – they stop people dying. ‘Some of these people will be old, some will be horrible people who would be better dead anyway, but a fair number of these are going to be in middle age with a reasonable chance of enjoying life. So this kind of thing is worth doing.’
The FDA were convinced, and the widespread use of aspirin for heart disease began. Worldwide, it saves more than 100,000 lives annually. Perhaps even more influentially, it demonstrated the power of marginal benefits and showed the statistical and scientific techniques needed to reliably detect them.
Clopidogrel’s minor advantages, heralded in Madrid, matter. ‘The inches we need are everywhere around us,’ declares Al Pacino’s football-coach apostle of small differences in Any Given Sunday. The history of aspirin teaches that small differences save lives, and some of those lives are worth saving. Clopidogrel is an inch better.
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