1998


From: Northwestern University

Anti-Clotting Drug May Cause Potentially Fatal Platelet Disorder

CHICAGO --- Ticlopidine, a drug that acts like aspirin and is widely used to prevent stroke as well as blood clot formation following placement of cardiac stents, can cause a rare but potentially deadly disease. The disorder, thrombotic thrombocytopenic purpura (TTP), generally develops within four weeks of starting ticlopidine therapy.

Symptoms of TTP include mass destruction of blood platelets, anemia, neurologic changes, progressive renal failure and fever. The cause is unknown, but in very uncommon cases, drugs other than ticlopidine, including penicillin, some anti-cancer drugs and oral contraceptives, have been associated with the syndrome.

TTP has been considered an extremely rare disorder -- less than four cases per million persons, with an overall death rate that was originally reported at 90 percent. With improvements in diagnosis and treatment, the mortality rate is now in the range of 10 to 20 percent.

However, a Northwestern University Medical School study has found that TTP as a side effect of ticlopidine occurs far more frequently than in the general population, and the mortality rate may be as high as 33 percent.

The Northwestern study also found that mortality was almost 50 percent for those older than 60, but only 16 percent in those younger than 60. One reason for the high death rate among patients who take ticlopidine for prevention of stroke is that the neurologic symptoms of TTP are similar to those of stroke.

In the past year, ticlopidine use has been expanded to include persons who undergo angioplasty and have a cardiac stent implanted during the procedure. Fifteen cases of ticlopidine-associated TTP were found in these patients, almost always presenting with acute onset of stroke-like symptoms, which facilitated the recognition of this life-threatening complication. Nonetheless, about one fifth of patients who received ticlopidine following cardiac stents died within four weeks of the procedure.

The study raises concerns over the potential for a rash of new cases of TTP following cardiac stent placement as well as underdiagnosis of ticlopidine-associated TTP and subsequent inadequate treatment, said Charles L. Bennett, M.D., a hematologist/oncologist and associate professor of medicine at the Medical School and Northwestern Memorial Hospital and the primary author of the study, published in the April 1 issue of the Annals of Internal Medicine.

Bennett said that most neurologists and cardiologists who prescribe ticlopidine are generally unaware of this side effect, which is described as "having a rare association" in the package insert produced by the pharmaceutical manufacturer, Hoffmann-LaRoche of Basel, Switzerland.

Ticlopidine's toxicity has raised concern since its approval by the Food and Drug Administration. Early clinical trials found that almost 3 percent of patients developed life-threatening bone marrow failure within the first three months of beginning therapy. Consequently, it has been recommended that blood tests be performed every two weeks for three months after starting on ticlopidine to identify this side effect early, before lethal complications develop. However, these tests do not help with early detection of TTP.

In the Northwestern study, 98 percent of the patients with TTP had had normal platelet counts within two weeks of diagnosis, Bennett noted. And almost all of them had been taking the drug for less than one month when TTP developed.

He said that the only proven way to lessen the chances of death for persons with ticlopidine-associated TTP is for patients to undergo plasmapheresis, a procedure that is similar to filtering the blood, immediately after the onset of the disease. Half the patients in this study who did not have plasmapheresis died, compared with a death rate of less than 25 percent in those who did.

The researchers also found that the older patients typically were not given plasmapheresis, and if they were, not quickly enough -- within the first three days of symptoms or admission to the hospital. The younger patients were nearly twice as likely to get plasmapheresis, to get it early and to survive.

The study was initiated after a personal friend of Bennett developed the rare side effect. His research group subsequently compiled clinical data on ticlopidine-associated TTP from at least 60 patients. Of these, almost two thirds were older than 60, half were male and around 70 percent had received ticlopidine for stroke prevention.

These cases were identified from five sources: reports from the FDA, previously published reports, case summaries from a survey of 20 hematologists, cases reported from a physician group specializing in plasma exchange and medical records of patients with this syndrome who had been treated at one of the Medical School's affiliated teaching hospitals.

Bennett said that this study also raises concern that additional measures by the FDA or the pharmaceutical company are likely to be needed to prevent additional deaths from ticlopidine.

His co-researchers were Peter D. Weinberg, Karine Rozenberg-Ben-Dror, Paul R. Yarnold, Hau C. Kwaan, M.D., professor of medicine, and David Green, M.D., professor of medicine, of the Institute for Health Services Research and Policy Studies; the Robert H. Lurie Cancer Center; the Chicago Veterans Administration HealthCare System-Lakeside Division; and the division of hematology/oncology, department of medicine, at the Medical School and at Northwestern Memorial Hospital.

3/30/98 -30-

(Editor's note: Dr. Bennett can be reached through his paging number: 888-242-4703)




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