By David N. Leff

George Washington died on Dec. 14, 1799, at 67 years of age. The cause of death was a massive, iatrogenic loss of blood.

His physician had bled him heavily four times, as therapy for the ex-president¿s high fever and acute laryngitis, brought on by a horseback ride in the snow.

Bloodletting ¿ phlebotomy to the medical trade ¿ had been a preferred treatment for millennia. Also known as ¿venesection¿ or ¿breathing a vein,¿ it was applied to virtually every disorder, from fever to apoplexy to lunacy, and was still practiced promiscuously late in the 19th century. (See BioWorld Today, June 24, 1994, p. 1.)

After tying a tourniquet around the upper arm, to make veins stand out, the practitioner stabbed one vessel with a sharp lancet. The rationale was to ¿cool the body,¿ made hot by an excess of blood. A popular alternative technology was to apply blood-sucking leeches all over the patient.

The leech of choice, Hirudo medicinalis, was a slug-shaped worm about 1.5 inches long when hungry, 6 inches when sated with mammalian blood. Once in place, three sharp teeth on its round sucker cut a V-shaped incision in the skin. Into the wound, the leech pumped its saliva, which contained an anesthetic, a blood-vessel dilator to increase flow, and an anti-clotting compound.

This blood-thinning protein, named hirudin, now exists in recombinant form. It takes its place alongside aspirin plus the anticoagulant heparin ¿ the standard two-drug combo for treating or preventing heart attacks brought on by clot buildup in atherosclerotic plaque, which causes coronary artery disease.

That well-tried combination is known to cut death rates and curb further heart attacks in people with unstable angina pectoris. This is a hallmark chest pain caused by insufficient blood traversing atherosclerosis-pinched coronary arteries.

But even with prompt aspirin/heparin treatment, 5 percent to 10 percent of patients go on to have a heart attack, or die in the hospital during the seven days following that therapy.

¿Unstable coronary disease,¿ pointed out Swedish cardiologist Lars Wallentin, ¿is an ideal clinical target for anti-thrombotic therapy, since most of the patients have a thrombotic coronary lesion as the main cause of the disease and a high risk of coronary events in the next few weeks.¿

The advent of recombinant hirudin confronted the cardiological community worldwide with a knotty question: Is the synthetic leech compound any better than heparin?

International Trial Enrolled 10,141 Patients

It took 10,141 patients at hospitals in 15 countries on six continents to come up with a preliminary answer. These individuals had been admitted within hours of a life-threatening cardiac episode. They were recruited between August 1996 and April 1998 in a randomized, double-blind, controlled clinical trial mounted by the ad hoc Organization to Assess Strategies for Ischemic Syndromes ¿ OASIS for short. Their report appears in The Lancet dated Feb. 6, 1999, under the title: ¿Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST [a brain-wave sign] elevation: a randomised trial.¿

The chairman and principal investigator on the OASIS Steering Committee is professor Salim Yusuf at McMaster University in Hamilton, Ontario. The trial, he said, showed that ¿hirudin is superior to heparin in preventing cardiovascular death, myocardial infarction and refractory angina, with an acceptable safety profile.¿

But a Lancet commentary on the OASIS study bears the more cautious title ¿New antithrombotic treatment in unstable coronary syndrome - for whom?¿ Its author, Wallentin, at the University Hospital in Uppsala, Sweden, demurred: ¿To fully assess the value of hirudin in unstable coronary disease,¿ he wrote, ¿its efficacy needs to be explored in higher-risk populations and for longer periods.¿

Unlike heparin, the paper explained, ¿hirudin interacts directly with thrombin [a key clot precursor], and inhibits clot-bound and circulating thrombin equally well. The recombinant hirudin was provided by its maker, Hoechst Marion Roussel AG, of Frankfurt, Germany, which funded the OASIS trial, along with other commercial sponsors. The companies, the OASIS co-authors footnoted, ¿had no access to any outcome data until the study was complete.¿

The mammoth OASIS study set out to test the hypothesis that ¿recombinant hirudin, a direct thrombin inhibitor, would be superior to heparin, an indirect thrombin inhibitor, in patients with acute ischaemic syndromes who were receiving aspirin.¿ Half of the 10,141 trial subjects got intravenous heparin, and half hirudin, infused over a 72-hour period.

Overall, hirudin scored 10 percent to 20 percent fewer deaths or infarctions than heparin.

At seven days, 213 (4.2 percent) of the heparin cohort, and 182 (3.6 percent) in the hirudin group, had either died of their cardiovascular disease or experienced a new myocardial infarction.

Between seven and 35 days after treatment, the heparin cohort suffered a further 175 deaths or infarctions; the hirudin group, 163. From day one to 35, these adverse events totaled 7.8 percent in the heparin patients, 6.8 percent in the hirudin recipients. More hirudin patients (7.6 percent) than heparin (4.5 percent) reported minor bleeding episodes. And there were 14 strokes in each cohort.

This ¿significant number of additional ischaemic events,¿ the paper points out, ¿suggests that longer-term anti-thrombotic treatment may have the potential to increase long-term benefit.¿ It also made the point that for hirudin¿s margin of superiority ¿to translate into clinically worthwhile differences, the absolute risk reductions are likely to be greater in higher-risk patients.¿

Will Clinical Guidelines Tilt Toward Hirudin?

Among the hundreds of hospitals in the OASIS trial was Rush Presbyterian-St. Luke¿s Medical Center in Chicago. Its director of coronary care at the time of the study, cardiologist James Calvin, told BioWorld Today: ¿Heparin is a standard therapy for unstable angina, which is recommended by current clinical-practice guidelines.

¿What OASIS did,¿ Calvin recalled, ¿was a head-to-head comparison of heparin vs. recombinant hirudin, and found with hirudin a significant reduction in clinical events. The implication here is that this particular drug can very well replace heparin as first-line therapy.

¿There¿s going to be a lot of debate, I suspect,¿ Calvin continued. ¿I would think that clinical-practice guidelines will be revised, that they might use low-molecular-weight heparin in lower-risk patients, and consider hirudin in at least moderate or higher-risk patients ¿ once it¿s approved by the FDA. n