Friday, February 24, 2012

The Aspirin Controversy

Based on a talk at Dr. Purser’s wellness group, Bradenton, FL

Aspirin, a widely used and easily available drug is as ubiquitous as Jell-O, both products got their present name around the same time in the year 1897. Ever since its formulation, aspirin has courted its share of controversy. Aspirin contains salicylate, which is derived from the Willow plant. Hippocrates, regarded as the father of Western Medicine first described the pain killing properties of Willow bark. These observations were also made by other civilizations down the ages until they were scientifically proven with modern day methods. The active pain killing ingredient in the Willow plant was isolated in 1826, which was then modified over the course of the next several decades. In 1897, Felix Hoffmann, a German chemist working for Bayer formulated aspirin in its present form. It almost did not make it to the market. A competing drug, heroin, was about to be launched by Bayer as a cough remedy. Luckily, someone important at Bayer was convinced of its healing properties having tried it on himself. Aspirin then made it to the market as a pain reliever. Several decades later, scientists discovered that the chemical innovations that led to the formulation of aspirin from salicylic acid were instrumental in aspirin’s role in preventing strokes and heart attacks. 

The symptoms of coronary artery disease were first described by William Herberden, an English physician in 1768. Since this initial description of the coronary artery disease, it took close to 200 years before aspirin was first used in the prevention and treatment of coronary artery disease. Although the link between angina and coronary artery disease were made several years after Heberden initially described it, some of his descriptions of the symptoms of heart disease hold true even in the current day.

“There is a disorder of the breast, marked with strong and peculiar symptoms considerable for the kind of danger belonging to it, and not extremely rare, of which I do not recollect any mention among medical authors. The seat of it, and sense of strangling and anxiety, with which it is attended, may make it not improperly be called Angina pectoris.

Those, who are afflicted with it, are seized while they are walking and more particularly when they walk soon after eating, with a painful and most disagreeable sensation in the breast, which seems as if it would take their life away, if it were to increase or to continue; the moment they stand still, all this uneasiness vanishes.”

Along with a better understanding of the symptoms of coronary artery disease, cholesterol plaques were then discovered in patients with heart attacks. It was only in 1950, that aspirin was first hypothesized to prevent heart attacks. The credit for this discovery goes not to a Nobel prize winning scientist but a general practitioner named Lawrence Craven. At that time, aspirin in the form of chewable gum was routinely given to patients for pain relief after surgery of the tonsils. At that time, bleeding after surgery was a very frequent complication. It was Craven who first made the connection between bleeding and aspirin gum. This led him to postulate that heart attacks which are caused by blood clots could potentially be prevented with aspirin therapy. Despite his research methods being rudimentary, he managed to follow 8000 patients who had taken aspirin daily and he found that there were no instances of patients having suffered a heart attack while on aspirin therapy. Based on this, he advocated prophylactic aspirin therapy for patients between 45-65 years of age. In line with his recommendations for his patients, he perhaps did not take aspirin himself in his later years as he died of a heart attack at age 74.

After aspirin was linked to bleeding, considerable research went into identifying the mechanism. This research centered on platelets which are particles in the blood stream that when clumped together starts the formation of a blood clot. There are millions of these tiny platelets moving in the blood stream. Despite continuously bumping into each other while travelling in the blood stream they do form a clot. A triggering mechanism makes platelets stick together.

The triggers and the resulting chemical cascade that makes individual platelets stick to each other and ultimately attracting a large mass of platelets to form a clot is fairly complex. For simplicity, this process can be broken down into two steps, each step being mediated by certain molecules. One molecular compound is involved in facilitating a small number of platelets attaching to one another.  Another molecular compound amplifies this process exponentially turning a process visible only under a microscope into a visible blood clot. Aspirin primarily blocks the first step and medications such as clopidogrel (plavix) block the second step. Since platelets are central to any clot formation, in the setting of a heart attack, using aspirin and clopidogrel (plavix) in combination makes sense as both these steps are blocked simultaneously. This combination of drugs is also very important when a hollow metal tube called a stent is placed during a heart attack to relieve a blood vessel blockage. Without these drugs, the metal in the stent can act as a trigger for the clumping of platelets.

Large scale clinical trials, have conclusively established the efficacy of aspirin in saving lives during and after a heart attack. The use of aspirin in this setting is known as secondary prevention. But what about the usefulness of aspirin in primary prevention which is preventing the first heart attack or stroke? The waters get muddy here. The most recent controversy about aspirin has centered around the role of aspirin in the primary prevention of heart disease.

In 2002, a group of experts from Oxford University studied all relevant published clinical trials pertaining to the use aspirin in cardiovascular disease. They published a paper that suggested a role for low dose aspirin in the prevention of heart attacks, particularly in men over the age of 50 with a couple of risk factors. The same group that was credited with establishing the role of aspirin in primary prevention reexamined this question again in 2009. Their finding was a dramatic turnaround from their initial recommendations. The benefits in preventing heart attacks was offset by higher bleeding rates, particularly in the gastrointestinal tract and the brain leaving no net benefit for the use of low dose aspirin. A more recent large scale study of over 100, 000 patients published this year confirmed this finding.

The current thinking is that aspirin is of proven benefit in the setting of a heart attack and stroke, both at the onset of the event and subsequently to prevent a recurrence. Aspirin has no net benefit in preventing heart attacks and strokes in someone who has never experienced one. One possible explanation for this is the fact that aspirin does not play any role in preventing the formation of blockages in the wall of blood vessels. This process takes years to form. On the contrary, changes in the blood vessel wall leading to a heart attack or a stroke occur rather quickly in the matter of minutes. It starts with the breakdown of a cholesterol laden blockage. If a small crack forms on the surface of the blockage exposed to the blood stream, the force of moving blood makes this crack bigger exposing a gaping hole. Platelets stick to the exposed parts of the cholesterol blockage and start to clump. Since aspirin prevents clumping of platelets, it is very useful in this setting.

Prevention of buildup of cholesterol rich particles in the walls of blood vessels is best prevented by diet, exercise, cholesterol lowering drugs and control of elevated blood pressure.