being produced and the incremental costs that are required to produce these benefits? If a therapy represents good value for the money, then the second question is whether there is money available to make the therapy generally available. Mark used the history of the development of t-PA (tissue plasminogen activator) to throw light on these two questions.

Mark outlined the development of thrombolytic therapy, streptokinase. In the 1980s, two very large RCTs were carried out in Europe to evaluate streptokinase. The ISIS2 trial was the second trial and was published in 1988. This trial showed that the combination of streptokinase therapy plus one aspirin taken in the emergency room lowered the mortality rate in heart attack patients from 13 percent to 8 percent. A paradigm shift in the treatment of heart attacks had been achieved. Instead of being a passive observer, cardiologists now had a therapy that could change the outcome for many heart attack patients.

Around this time Genentech developed recombinant t-PA. By 1985, the NIH had conducted the TIMI1 trial, which had shown that at 90 minutes after the onset of a heart attack the t-PA drug had twice as many open infarct arteries as the streptokinase drug. This was regarded as a major advance in the care of acute myocardial infarction patients. Treatment had gone from a low-tech bacterial enzyme (streptokinase) to a high-tech genetically engineered product (tissue plasminogen activator). In the United States, no trial was carried out to evaluate the mortality benefits of t-PA. Since the drug opened more arteries there seemed no question that patients would live longer.

In a more skeptical Europe, two large-scale trials, GC2 and ISIS3, were carried out. Both of these trials found that t-PA and streptokinase were equivalent in mortality rates. This was a shock to U.S cardiologists and it had a serious negative effect on the market share of t-PA. At the time of the GC2 and ISIS3 trials t-PA had a U.S market share of about 70 percent, with streptokinase having the remaining market share. t-PA’s market share dropped to 55 percent and at this point Genentech decided to fund the GUSTO-1 trial comparing streptokinase with t-PA. This 40,000 patient trial showed that the streptokinase patients at 30 days had a 7.3 percent mortality rate and the t-PA patients had a 6.3 percent mortality rate. At the time the streptokinase treatment cost about $300 while the t-PA treatment cost about $2,200, a seven-fold difference in price. Subsequent cost-effectiveness analysis showed that t-PA provided an extra life year at an estimated cost of $33,000 (Mark et al., 1995; Mark, in press). As a result of this analysis, t-PA was judged to be an economically attractive therapy. Recombinant thrombolytic agents (t-PA and others) now have 96 percent of the U.S. market with streptokinase having just 4 percent.

On a national level the economic cost of shifting from streptokinase to recombinant thrombolytic agents has been significant. Assuming there are



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