Antithrombotics
During the 1950s, pioneering research work in the area of blood coagulation was carried out by Professor Gwyn Macfarlane and Dr Rosemary Biggs in the MRC Blood Coagulation Unit at the Churchill Hospital in Oxford1. Haemophilia B, the second most common form of haemophilia, was first identified here, and takes its alternative name of Christmas disease from the surname of the young patient studied in 1952.
By this time, antithrombotic drugs, which interfere with blood clotting in blood vessels, had become available. A blood clotting system is essential to prevent bleeding after injury outside or inside the body. But when clotting occurs inside arteries and veins, which can happen spontaneously, the clots may cause problems such as cutting off the vital blood supply to body organs.
Heparin and warfarin
Heparin, an antithrombotic drug, was discovered in 1916 in the US, but it was not practically applied by doctors until the early 1930s, when the researchers developed a method to make a purified, plentiful and inexpensive supply for human use. The first human trials began in 1935 and heparin as well as warfarin a drug with similar action emerged as an anti-clotting treatment in the 1940s and 1950s. Low molecular weight heparin (natural heparin consists of molecules of varying sizes) has now largely replaced the original preparations.
Both heparin and warfarin interfere with the production of fibrin, which is the insoluble substance in clots. They are dangerous if the dose is too large, as spontaneous bleeding may occur. In particular, warfarin requires constant monitoring and dietary control physicians have therefore been wary of using it, partly put off by the fact that it has been used as a rat poison. However, trials that ran from the late 1950s until the 1980s, some of which were funded by the MRC, showed that warfarin was effective in secondary prevention lowering the death rate of people who had already had a heart attack.
Warfarin was also tested for primary prevention of heart attacks, and work at the MRC Epidemiology and Medical Care Unit in London showed that a low dose of the drug substantially lowered the death rate2. Warfarin also reduces the risk of having a stroke in people with atrial fibrillation a fast and erratic heartbeat which can cause the blood to pool in the upper chamber of the heart called the atrium, making it more like to clot, break away and cut off part of the blood supply to the brain3. Trials showed that warfarin can reduce the risk of a first or second stroke by up to 70 per cent. Currently, there is an MRC-funded trial in Birmingham comparing warfarin with aspirin for stroke prevention in elderly people. Warfarin is also used in heart valve surgery and has saved many lives this way.
Aspirin an anti-clotting drug
Platelet active agents, such as aspirin and clopidogrel, are another class of antithrombotic drugs. They interfere with the way platelets behave and stop them clumping together. In the 1970s, aspirin was found to be effective in secondary prevention4. The incidence of recurrent heart attack is very high during the first year after a heart attack, and treatment with aspirin saves many lives, even though some episodes of serious bleeding occur. Aspirin also works for primary prevention in high-risk people, but should be avoided in those with low risk.
Recently, Australian scientists have shown that low-dose aspirin during pregnancy could cut the risk of the condition pre-eclampsia, which threatens the lives of mothers and babies by raising blood pressure and causing strokes5. The team reviewed 31 trials involving more than 32,000 women and concluded that aspirin lowered the risk of pre-eclampsia by 10 per cent. It is thought that aspirin may improve defective blood clotting and blood flow, which affect the placenta in women with the condition.
Dissolving clots
Thrombolytic agents, such as streptokinase, dissolve clots directly. In the 1960s and 1970s, there were some small, unreliable trials with streptokinase. Then, in 1988, the MRC-funded Clinical Trial Service Unit in Oxford published a breakthrough trial called ISIS-2 (International Study of Infarct Survival)6. The study tested a new approach of using aspirin and streptokinase in combination immediately after a heart attack. The use of either streptokinase or aspirin alone reduced the risk of vascular events by 25 per cent, but the two together decreased the risk by 50 per cent.
Professor Tom Meade, at the London School of Hygiene and Tropical Medicine, says: This changed clinical practice almost overnight. The new treatment saved hundreds of thousands of lives and became the standard treatment for the first few hours following a heart attack. The MRC is currently funding a trial to investigate the use of thrombolytic agents in patients within six hours of a stroke and in older people, an age group who were not included in earlier trials.
In the veins
Anticoagulant drugs are also used for venous conditions there have been trials of aspirin, heparin and warfarin for deep vein thrombosis (DVT), which can give rise to a condition called pulmonary embolism. This is caused by a blood clot obstructing the blood supply to the lungs. Heparin is recommended for use in high-risk situations, such as long air journeys, surgery, immobilisation, pregnancy in women at high risk of pulmonary embolism and hereditary conditions that cause the blood to clot. The MRC is funding a trial called CLOTS which is testing a non-drug treatment stockings to prevent DVT.
References
1. Biggs et al. (1953). The initial stages of blood coagulation. J Physiology, 122, 538.
2. The Medical Research Councils general Practice Research Framework (1998). Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Lancet, 351, 233.
3. Rash et al. (2006). A randomised controlled trial of warfarin versus aspirin for stroke prevention in octogenarians with atrial fibrillation (WASPO). Age Ageing, 0, afl129v1-0.
4. Elwood et al. (1974). A randomised controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. BMJ, 1, 436.
5. Askie et al. (2007). Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet, Epub ahead of print.
6. Baigent et al. (1998). ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. BMJ, 316, 1337.
MRC September 2006, updated May 2007.