Cardiologists from key academic, private and public hospitalssay their opinions about t-PA are unaffected by debate overhow the anti-coagulent heparin is administered duringthrombolytic treatment.

The cardiologists from four leading medical facilities toldBioWorld that the ISIS-3 study of thrombolytic drugs was notflawed by the manner in which the anti-coagulant wasadministered to heart attack patients.

ISIS-3, released earlier this month, showed that streptokinase(SK) was equally effective and led to fewer strokes due tocerebral bleeding than either tissue plasminogen activator (t-PA) or Eminase, more expensive drugs to which strepotkinasewas compared. Half of the 46,000 patients received heparin todetermine whether the anti-coagulant improved the efficacy ofthe clot-busting thrombolytics.

The study has been viewed as important to Genentech Inc.,whose Activase is the only t-PA approved for use in the UnitedStates and holds about 64 percent of the thrombolytic drugmarket.

Genentech has said that ISIS-3 patients should have receivedheparin intravenously (IV) throughout thrombolytic treatmentrather than through subcutaneous injections, which werestarted four hours after treatment began. Genentech said thatat least 95 percent of U.S. physicians administer heparinaccording to the IV protocol.

Dr. Peter Mahrer, chief of cardiology at Kaiser Permanente LosAngeles Medical Center, told BioWorld that the mode of heparinadministration "had no effect whatsoever" on the ISIS-3results. The other cardiologists interviewed, all of whosehospitals and clinics have participated in ISIS-3 or other trialsof clot busters, agreed that this issue did not affect their choiceof streptokinase as their preferred drug.

The cardiologists, however, did have other opinions about themode of heparin administration.

Dr. Kanu Chatterjee, director of the Cardiac Care Unit at theUniversity of California, San Francisco, said the risks of IVadministration will cancel out any potential benefits. Althoughearly IV administration of heparin might prevent new clotformation, it might also increase the rate of cerebral bleedingleading to strokes, he said.

Dr. Steven Nissan, director of coronary care at the University ofKentucky in Lexington, said 3,000 U.S. patients in the ISIS-3study received IV heparin with either t-PA or streptokinase. Inthis group, the incidence of cerebral bleeding was seven timesas high in patients receiving t-PA than in those receiving SK.These results, Nissan said, do not justify the use of IV heparinand do not indicate that IV heparin improves t-PA'sperformance.

Kaiser PermanenteLs Mahrer also has reservations aboutadministering IV heparin with t-PA since t-PA alone leads totwice as much bleeding in the brain as does SK. Heparin maycompound the problem, he said.

Mahrer also said Genentech's claim that 95 percent of U.S.physicians use the IV heparin protocol is "grossly exaggerated."

Intravenous heparin has become part of the standard protocolfor t-PA treatment, said Mahrer, because it was part of theoriginal research protocol to test Activase in clinical trials. Hepredicted that future studies will change the method in whichheparin is administered.

Genentech spokesman Jack Murphy reiterated that thecompanyLs market surveys show that more than 95 percent ofcardiologists use IV heparin. The American College ofCardiology and the American Heart Association bothrecommend the IV mode of heparin administration, he added.

Dr. Douglas Triffon, a cardiologist at the Division ofCardiovascular Diseases at Scripps Clinic and ResearchFoundation in La Jolla, Calif., said the heparin controversy willlast until IV and subcutaneous injection protocols are testedside by side. He speculated that t-PA's shorter half-life in thebody might necessitate the use of the anti-coagulant to keepblood vessels open.

Triffon said that a comparison trial should also investigate theeffect of Lopressor, a beta-blocker drug that slows the heartrate and lowers blood pressure. Triffon said that patientsreceiving Lopressor in one of the early t-PA clinical trialsshowed no cerebral bleeding. He proposes testing Lopressor inconjunction with IV heparin and t-PA.031991ISIS3

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

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