Anticoagulants

Researcher name: 
Jack Hirsh, MD

The standard blood thinners are heparin and warfarin. Both are very effective but they have the limitation that they can produce serious bleeding. Our research has been directed at producing safer blood thinners

For the past 20 years, our group has been interested in developing safer, more effective and more cost-effective anticoagulants. Anticoagulants are blood thinners which are widely used to counteract abnormal blood clotting, which is the underlying cause of heart attacks, stroke and clots in the leg veins. Collectively, these disorders are the commonest cause of death and disability in the Canadian population.

The standard blood thinners are heparin and warfarin. Both are very effective but they have the limitation that they can produce serious bleeding. Our research has been directed at producing safer blood thinners.

In Search for Safer Heparins: The story of the development of the new heparins, low molecular weight heparins (LMWHs), began in the early 1970s. We were studying the optimal way to deliver heparin in an experimental rabbit model when by chance we noted that a fragment of heparin which was about a third of the size of standard heparin produced less bleeding for an equivalent anti-clotting effect. This was followed by 10 years of experimental work, which was supported by the Medical Research Council (MRC) and the Canadian and Ontario Heart and Stroke Foundations, to work out the mechanism of this promising effect. During the course of these studies, we and scientists in Europe confirmed the lower bleeding risk observed with LMWHs, determined the mechanism of this effect, and noted that LMWHs had other important potential advantages over standard heparin. Thus LMWHs are effective if given as one injection per day and have a more predictable anticoagulant response than standard heparin, which allows them to be given out of hospital without the need for complicated laboratory monitoring. The international pharmaceutical industry became interested and five different forms of LMWHs were patented by different companies and made available for clinical trials. Clinical trials began in the mid 1980s and our group was in the forefront, performing clinical trial following hip surgery (3 trials) stroke (2 trials) and knee surgery (1 trial). The results showed that LMWHs were safe and approximately twice as effective as standard heparin. LMWHs have been approved for use in most countries in Europe where they are used to prevent abnormal clotting in a broad range of medical and surgical patients. They are currently under review at the Canadian Health Protection Branch. Perhaps the most exciting application of LMWHs derives from the observation that they can be given in a fixed dose without the need for complicated laboratory monitoring. We are exploiting this property to investigate their use to treat patients with blood clots, in their homes, with subcutaneous injections (self administered) rather than in hospital. Because standard heparin needs to be monitored carefully by laboratory tests, patients with blood clots are currently admitted to hospital for 7 to 10 days. We feel that the need for hospital admission can be avoided in many such patients by substituting LMWHs for standard heparin and so reduce the cost and improve the safety and convenience of treating an important group of patients with abnormal blood clotting.

A large part of this work was performed at McMaster University by a multidisciplinary team including basic scientists (Drs. F. Ofosu, M. Buchanan), clinicians (Drs. A.G.G. Turpie, M. Levine, R. Hull), biostatisticians (Prof. M. Gent) and approximately 10 visiting scientists and research fellows who were supported by either the MRC or Heart and Stroke Foundation of Ontario. LMWHs took 20 years to develop from laboratory bench to bedside. Much of the work was done in Canada. They are the first new class of blood thinners to be developed to treat patients with abnormal clotting since heparin and warfarin were introduced approximately 50 years ago.

Lowering the Dose of Warfarin and Increasing its Safety: The second blood thinner in common clinical use is warfarin and coumarin. This is the active component of rat poison. Unlike heparin which must be given by injection, warfarin is given as a tablet (orally) and, therefore, usually prescribed when blood thinners are required for months, years or indefinitely. These blood thinners are used in ambulant (non-hospitalized) patients with clots in their legs, with irregularities of heart rhythm, disease of heart valves, with artificial heart valves and in selected patients who have suffered a heart attack. Although effective, warfarin in the doses used in North America until the last 7-8 years produced clinically important bleeding in 10-20% of patients. In the last 8 years, our group performed two clinical trials which demonstrated that a new low dose warfarin treatment regiment is just as effective as the accepted standard dose regimens but that it is associated with a dramatic five-fold reduction in bleeding. These studies led to the establishment of a special committee of the American College of Chest Physicians which recommended our low dose regimen for most patients requiring oral anticoagulants. Our two studies also stimulated other international studies which confirmed the effectiveness and much greater safety of the low dose concept. The impact on patient care has been enormous. Many patients with heart conditions who were denied long-term anticoagulants in the past because of the high risk of bleeding are now enjoying the benefit of the effective treatment. The low dose concept has been accepted by the medical profession world-wide. Its use has resulted in a 60-70% reduction in stroke in patients with certain cardiac disorders (heart irregularities) with a minimal risk of bleeding. We are now being supported by the Heart and Stroke Foundation of Ontario to see whether the combination of low dose warfarin and low dose aspirin is more effective than low dose warfarin in preventing stroke in patients with artificial heart valves.