Cardiologists from leading academic, private and publichospitals and clinics said they prefer streptokinase over t-PAin the treatment of most heart attack patients.

A sampling of key cardiologists suggests that the ISIS-3thrombolytic studies have established streptokinase (SK) as astandard that could erode the dominance of tissue plasminogenactivator (t-PA) as the nation's best-selling thrombolytic drug.

The cardiologists contacted by BioWorld said they preferstreptokinase over t-PA based on studies like ISIS-3. That46,000-patient multinational study, released earlier thismonth, showed that SK is as effective as either t-PA or anotherthrombolytic, Eminase, and is less likely to cause strokes.

The cardiologists, all of whose hospitals and clinics haveparticipated in ISIS-3 or other clinical trials of clot busters, alsovoiced strong opinions about how the anticoagulant heparin isadministered during thrombolytic treatments.

Dr. Peter Mahrer, chief of cardiology at Kaiser Permanente LosAngeles Medical Center, the nation's largest HMO, said thatKaiser recommends that its doctors use SK, which at $200 perdose is about one-tenth the cost of either SmithKline Beecham'sAPSAC (Eminase) at $1,700 or Genentech's Activase (t-PA) at$2,200.

Three years ago, said Mahrer, Kaiser's cardiology committeerecommended the use of SK in many cases while they waitedfor large clinical trials to indicate t-PA's value.

ISIS-3, which included 100 Kaiser Permanente patients,presented no evidence of t-PA's superiority, said Mahrer. Headded, "Kaiser is now revising its thrombolytic protocol toenforce even more rigidly the use of SK except in specialcircumstances."

Claims that ISIS-3 is flawed are "cries in the wilderness"probably intended for Genentech Inc. stockholders, Mahreradded.

Genentech, which has the only t-PA approved for use in theUnited States, has tried to distance itself from ISIS-3. Thecompany has argued that the results can't be applied to itsActivase because the study used a different form of t-PA,called duteplase (see sidebar).

However, in practical terms, the opinions by cardiologistsinterviewed about t-PA will result in decisions not to useActivase.

Dr. Kanu Chatterjee, director of the Cardiac Care Unit at theUniversity of California, San Francisco, said SK will be used forall patients at UCSF unless there are contraindications. "Due tothe tremendous difference in cost," Chatterjee added, "it istremendously difficult to justify the use of t-PA over SK."

Dr. Steven Nissan, director of coronary care at the University ofKentucky, said ISIS-3 has "set cardiology on its ears and hasexposed a souped-up genetically engineered drug that's a dog."Although he would have used t-PA in the past, Nissan nowplans to use SK.

Nissan said t-PA's defenders "can't keep fighting theoverwhelming data" that SK and t-PA show equal mortalitydata and that t-PA causes twice as much cerebral bleeding,leading to strokes. Nissan added that "it has cost more than $1billion to learn the hard way that high biotech does not alwaysmake a better drug."

Nissan predicted that t-PA will lose market share as word ofthe study trickles down through continuing-educationprograms.

Dr. Steve Gerber, a cardiologist who is an analyst withOppenheimer & Co., predicts that Activase's market share willdecline slowly to about 50 percent from 64 percent.Streptokinase now has 25 percent of the market. The otherdrug studied in ISIS-3, Eminase, has about 9 percent.

However, said Gerber, Genentech's sales may actually benefitfrom the growth of the thrombolytic market. Nissan estimatesthat 20 percent of heart attack patients receive thrombolytictreatments.

Gerber also said that doctors in private practice may takelonger to switch from t-PA to SK than will the more cost-conscious HMOs, preferred provider plans and government-supported health care programs.

Dr. Douglas Triffon, a cardiologist at the Division ofCardiovascular Diseases at Scripps Clinic and ResearchFoundation in La Jolla, Calif., had been using t-PA. Based on thestudies, he said, he will use SK on his next patient.

Triffon said his decision is based on SK's equal efficacy, lowerrate of cerebral bleeding and lower cost. He had used t-PA forits ability to open blood vessels more rapidly and its lowerincidence of allergic reactions, hypotension and fever. Fear ofcerebral bleeding has led him to switch to SK.

Insurance companies have applied no pressure to use thecheaper drug, said Triffon.

Blue Cross of California does not recommend which drugsphysicians should use to treat patients suffering heart attacks,said spokesman Michael Chee. He said the company does notwant to impede the use of any drug deemed necessary by thephysician. At this point, "thrombolytic drug costs do not comeinto play," Chee added.

Illinois regional Blue Cross/Blue Shield also pays for t-PAbecause it is a Food and Drug Administration-approved drug,said BC/BS spokesman Al Limburg. "In light of ISIS-3, however,we are reviewing the situation," he added.

Genentech spokesman Jack Murphy told BioWorld that thecompany last year had predicted that ISIS-3 would createcompetitive pressure and that t-PA sales, which were $210million in 1990, would stay even but would not grow. He said itis too early to evaluate the impact of ISIS-3 on drug sales. Itwill take time to see what all cardiologists decide, Murphyadded.

TUESDAY: Cardiologists discuss the heparin issue.


There are two physical differences between the Genentechtissue plasminogen activator, Activase, and the BurroughsWellcome t-PA, duteplase, which was used in the ISIS-3 studyof thrombolytic therapies:

-- Duteplase has a different amino acid than Activase at onepart of the protein chain.

-- Duteplase is a double polypeptide chain of t-PA whileActivase is a single-chained t-PA.

The debate over ISIS-3 reflects a big difference of opinion overwhat those two physical differences signify.

But both companies agree on the physical differences of theproteins. The double duteplase chain is formed from a singlechain by enzymatic clipping of the protein. Both single- anddouble-chain t-PAs are held together by disulfide bonds.Scientists think that in the body, single-chain t-PA is convertedto double-chain t-PA before t-PA carries out its clot-bustingactivities.

There are no side-to-side comparative clinical studies todirectly compare the two forms, said cardiologist andOppenheimer & Co. analyst Dr. Steve Gerber. Published studiesconflict as to whether the two forms are functionally similar invitro with respect to half-life in serum, clot-binding ability andthrombolytic activity. -- CTV


-- Carol Talkington Verser, Ph.D. Special to BioWorld Part 1 of 2

(c) 1997 American Health Consultants. All rights reserved.