Stroke and the pharmaceutical industry

Medicines that dissolve blood clots

‘Clot-busters’ either digest fibrin fibres directly or activate natural mechanisms for doing so. The restoration of blood flow as soon as possible after stroke is crucial if brain damage is to be minimised. This is why it is so important to get someone who has had a stroke to hospital and to differentiate those with an ischaemic stroke from those with an haemorrhagic stroke. Clot-busters can be used in the former, but would be dangerous in the latter because they might perpetuate the bleeding.

Several clot-busting medicines have been developed, including streptokinase (Pharmacia & Upjohn and Hoechst Marion Roussel), urokinase (Leo Pharmaceuticals and Serono), and alteplase (Boehringer Ingelheim), which is a recombinant tissue plasminogen activator (rt-PA). So far, alteplase is on the market only in the USA for the treatment of acute stroke within three hours, but it is expected to be available in Europe shortly. Both streptokinase and urokinase are marketed for other forms of thrombosis, including heart attack and deep vein thrombosis. Alteplase is available for heart attack and pulmonary embolism, but not deep vein thrombosis.

Clinical trials to test the use of these agents in stroke have a history of over 40 years, but early trials were disappointing. Better designed and controlled trials have been conducted in the last 18 years, but there is still considerable debate regarding the risk-benefit ratio, and individual trial results have often been conflicting. A recent overview of 12 trials concluded that streptokinase carried a significant risk of causing brain haemorrhage. In fact, some recent trials of streptokinase were stopped early because of the high number of brain haemorrhages and for the present its use in stroke has to be questioned.

By contrast, an overall favourable benefit was shown for alteplase in terms of the return to independence of people who had a stroke. A major trial of alteplase (the NINDS Trial) published in 1995 concluded that the medicine resulted in a significantly improved chance of minimum or no disability at 3 months in people given the medicine compared with placebo, but there was still an increase in the risk of cerebral bleeding causing additional symptoms. On balance, the advantages were considered to outweigh the disadvantages and the compound was granted a licence by the US authorities in 1996.

A European study also published in 1995 (the ECASS-I Study) confirmed significant benefits in some people compared with placebo – the overall neurological status was better at day 90 and hospital stays shorter. However, the study concluded that the risk to benefit ratio of the medicine was only acceptable in some people with moderate to severe stroke. If these individuals can be identified early by CT scans, then alteplase can greatly improve their prospects.

The most recent European Trial (ECASS-II), published in 1998, supported the view that alteplase has a part to play in the routine management of ischaemic stroke when given to people within three hours of symptoms appearing. However, it should only be used in hospitals experienced in the effects of ‘clot-busting’ medicines.

The status of the people who took part in the NINDS trial after one year showed that the benefit was sustained, while CT scans showed that treatment led to a reduction in the volume of brain damage by nearly 40 per cent at three months. Reports of its wider use have also been encouraging. However, the decision to treat with alteplase is a hard one for doctors and especially the individual and their family, who have to weigh up the risks against the benefits.