Garret FitzGerald's research showed the effectiveness of using low-dose aspirin to reduce the risk of heart attack and proved that some painkillers could increase that risk, writes Dick Ahlstrom.
Prof Garret FitzGerald's work has been central to the widespread use of low-dose aspirin as a way to reduce heart attacks. His groundbreaking research also showed how the long-term use of certain popular painkillers could slightly increase the risk of heart attack in some people taking them on a regular basis.
"Many, many people contribute to the formation of a concept and the acquisition of a proof that ultimately leads to a therapy," FitzGerald says. Other researchers made the initial link between aspirin and reduced cardiovascular risk and did the later large-scale trials that showed aspirin worked.
"We filled in that gap in between," says FitzGerald, again citing colleagues who worked in the same area. It was a significant gap, however, the biochemistry that explained how the use of low-dose aspirin could help diminish the risk of blood clots and the incidence of stroke and heart attack.
When the benefits of aspirin in this context were first identified, the gains in terms of heart risk were significantly eroded by the damage that aspirin can cause to the stomach. Patients had fewer heart attacks but more stomach ulcers and other gastric difficulties.
"It illustrates how any drug that is useful will also have unwanted effects as well," FitzGerald says.
His work helped show how aspirin could reduce heart attack and stroke by a quarter to a third "while minimising the unwanted effects, particularly bleeding from the gut, by reducing the dose". Low-dose aspirin is now taken therapeutically by millions of people around the world.
FitzGerald and his team at the University of Pennsylvania in Philadelphia also made the enormously important discovery that some of the most widely used pain-relievers in the world could block the benefits coming from low-dose aspirin. These included the popular ibuprofen and also two specifically chosen for use by patients with arthritis: Vioxx and Celebrex.
These drugs are known as "COX-2 inhibitors" because they block the function of the enzyme COX-2. The COX protein comes in two forms, 1 and 2. COX-1 is essential for blood clotting and aspirin acts to block it, thus thinning the blood.
COX-2 is linked to the inflammation typical of arthritis, and ibuprofen, Vioxx and Celebrex inhibit this. When this association was discovered, the drug companies rushed to produce COX-2 inhibitors as a way to block the pain of arthritis, producing a financial "bonanza", FitzGerald says.
His group discovered, however, that these drugs also attach to COX-1, as a consequence preventing aspirin from attaching. This stopped aspirin's ability to reduce clotting, so patients hoping to reduce their risk of the clots that cause heart attacks got no benefit at all.
He published his findings on ibuprofen in January 1999 and warned at that time that other COX-2 inhibitors would have the same effect. The drug companies denied that this was so, that their products had the potential to slightly increase the risk of cardiac events.
Last October, Merck & Co did withdraw its drug Vioxx from the market. It had been its biggest seller, with estimated annual sales worth €2,000 million.
"I think what we showed was how aspirin could bring benefits and how COX-2 drugs could cause harm. In our more recent work we have shown that one can retain much of the benefit of COX-2 inhibitors and reduce the risk of cardiovascular events," says FitzGerald.
He also explained all the biochemistry behind it, how COX-2 turns off proteins called prostaglandins.
"The same prostaglandins you were turning off were playing a preventative role in the cardiovascular system," he says.
FitzGerald has had a profound impact on our understanding of how this family of drugs works in the body, both to block pain but also help or hinder cardiovascular health. The Boyle Medal award celebrates the excellence of his research effort.