Aspirin May Be Better Than Ticlopidine for Recurrent Stroke Prevention in African Americans

Laurie Barclay, MD

June 10, 2003

June 10, 2003 — Ticlopidine (Ticlid; Roche) does not appear to be superior to aspirin in preventing recurrent strokes in African-American patients, according to the results of the African American Antiplatelet Stroke Prevention Study (AAASPS), published in the June 11 issue of The Journal of the American Medical Association.

Physicians should not go beyond the data, however, the researchers say. Aspirin should be considered as initial treatment for appropriate patients, but those who have done well on ticlopidine should not necessarily be switched.

"We had anticipated that ticlopidine would be more effective than aspirin in our African-American study participants. However, this was not the case," lead author Philip B. Gorelick, MD, MPH, FACP, Jannotta Presidential Professor of Neurology at Rush Medical College in Chicago, Illinois, told Medscape. "Based on the AAASPS data, we have concluded that aspirin is a better treatment than ticlopidine for aspirin-tolerant, African-American, noncardioembolic ischemic stroke patients."

Mortality from and incidence of stroke are about twice as high in African-American patients as they are in other patients, and they also have a higher prevalence of risk factors for stroke and cardiovascular disease, including hypertension, diabetes mellitus, cigarette use, and obesity. Yet African Americans have been underrepresented in previous clinical trials of antiplatelet therapy. Earlier studies suggesting an advantage of ticlopidine over aspirin enrolled very few African Americans.

"AAASPS is an historic study as it is the first clinical trial to address the disproportionate stroke burden among African Americans," Dr. Gorelick said. "Because African Americans generally have had less access to medical care, medical procedures, and underrepresentation in clinical trials, in preparation for AAASPS we established support from African-American leaders, community organizations, and churches and established an African-American community advisory board to assist us in issues relating to recruitment and retention of study participants and overall design of the study."

Analysis of data from the earlier Ticlopidine Aspirin Stroke Study (TASS) suggested that nonwhite subjects might benefit from ticlopidine more substantially than from aspirin for stroke prevention and might experience fewer adverse effects compared with white subjects. However, the study lacked sufficient statistical power to reach any definite conclusions because of the relatively small number of nonwhite subjects.

Dr. Gorelick's group therefore designed AAASPS to have adequate statistical power to determine if ticlopidine was more beneficial than aspirin in a focused clinical trial for African Americans.

"This was a very large, well coordinated study of a very important population subgroup at high risk for stroke, namely African Americans," Ralph L. Sacco, MS, MD, author of an accompanying editorial and a professor of neurology and epidemiology at Columbia University–New York Presbyterian Hospital, told Medscape. "Earlier studies suggested that [ticlopidine] might be better than aspirin in terms of lowering risk of recurrent stroke, but in this study, it was not substantially better and might even be a little worse."

From December 1992 to October 2001, this double-blind, multicenter trial randomized 1,809 African-American adults with recent noncardioembolic ischemic stroke to receive either 500 mg ticlopidine or 650 mg aspirin daily. Subjects were examined at baseline, every two weeks during the first three months, at six months and every four months thereafter for 24 months, and at other times if indicated for patient safety.

The composite primary outcome of recurrent stroke, myocardial infarction, or vascular death occurred in 133 patients (14.7%) receiving ticlopidine and in 112 patients (12.3%) receiving aspirin (hazard ratio [HR], 1.22; 95% confidence interval [CI], 0.94 - 1.57). Although this trend for fewer primary outcome events in the aspirin treatment group was not statistically significant, the results for the secondary outcome of recurrent stroke approached statistical significance in favor of aspirin ( P = .08).

Contrary to expectations, statistical analyses at six and a half years showed that the probability of ticlopidine being superior to aspirin in the prevention of the primary outcome endpoint was less than 1%. The blinded phase of the study was therefore terminated at the recommendation of the Data and Safety Monitoring Board appointed by the National Institutes of Health.

If the trial were allowed to continue to completion, statistical analyses revealed a 40% to 50% probability of aspirin being significantly better than ticlopidine in reducing the risk of recurrent fatal or nonfatal stroke.

Serious neutropenia occurred in 3.4% of patients receiving ticlopidine and in 2.2% of patients receiving aspirin ( P = .12), and thrombocytopenia occurred in 0.3% vs. 0.2%, respectively ( P = .69). One patient receiving ticlopidine developed thrombocytopenia, thought to be possible thrombotic thrombocytopenic purpura; the patient recovered with plasmapheresis.

These findings raise three important questions: (1) Why did the results of AAASPS differ from those of TASS? (2) Why do African Americans appear to respond differently than whites to different antiplatelet agents? and (3) How can physicians best protect African Americans from the consequences of their greater vulnerability to stroke?

"AAASPS used a different dose of aspirin than in TASS and was carried out in a later time period in which more sophisticated stroke and cardiovacular disease preventives were available," Dr. Gorelick said. Another possible reason he cited for the different findings is that AAASPS was statistically powered to address the main study hypothesis, but TASS lacked sufficient power to address recurrent stroke prevention in nonwhites.

"We still have no explanation for the differential response of blacks and whites," Dr. Sacco says. "In fact, we still can't be sure that the response is different, because no whites were included in the AAASPS study."

According to Robert Arora, MD, a professor of medicine and pharmacology at the University of Medicine and Dentistry of New Jersey in Newark, genetic differences may underlie increased susceptibility to stroke in African Americans and their varied responses to antiplatelet agents.

"[Ticlopidine] and aspirin have different mechanisms of antiplatelet action," said Dr. Arora, who was not involved in AAASPS. "Genetic polymorphisms may influence which class of antiplatelet drug is likely to be more effective."

"More research is needed to determine possible pharmacogenetic and other pharmacologic differences by race-ethnic group," Dr. Gorelick said. "Overall, there has been a paucity of such study in blacks."

In designing such studies, Dr. Arora suggests careful delineation of racial makeup, as genetic factors influencing stroke and cardiovascular disease risk in Caribbean blacks may differ from those in blacks of African descent. Similarly, African Americans with Hispanic components in their ancestry may have important genetic differences from those without this ethic blend. Further compounding the problem is that studies may lump together individuals of disparate racial backgrounds in a single category.

So what are the practical implications of this study for preventing recurrent stroke in African-American patients?

"What we can say from this study is that in a new African-American stroke patient, we wouldn't use [ticlopidine]," Dr. Sacco says. "We will now have to re-evaluate how to manage an African-American patient who has been stable on [ticlopidine] for many years."

Dr. Sacco warns that findings from this study cannot be extrapolated beyond the two-year follow-up period. "It comes down to a matter of judgment, which has to be individualized for each patient," he says. "If side effects or financial factors become a problem on [ticlopidine], you could switch to aspirin. On the other hand, if they've been doing well for years, it's hard to make the argument to take them off."

Stroke continues to have a disproportionately severe impact on the African-American population because there is excess mortality from stroke among African Americans despite recent declines in overall stroke mortality. The Greater Cincinnati Stroke Study, the Baltimore Washington Cooperative Study, and the Northern Manhattan Study have all shown two- to three-fold greater stroke incidence rates for African Americans than whites in the same communities.

Dr. Arora said increased stroke risk in African-Americans are due to such factors as increased prevalence of cardiovascular risk factors, socioeconomic factors limiting access to healthcare, and genetic factors. Given African Americans' high risk for cardiovascular and cerebrovascular disease, Dr. Sacco urges physicians to be particularly aggressive about stroke prevention in this group.

"We face a major challenge in treating the African-American population, which was highlighted even in this study, and we need to do better to try to decrease the incidence of stroke," Dr. Sacco said. "It's important for physicians to realize that antiplatelet agents are just one way to prevent recurrent stroke, and that they have to be equally concerned about controlling cardiovascular risk factors like hypertension, diabetes, and obesity."

AAASPS was not designed specifically to address the issue of other antiplatelet agents, such as the combination of aspirin plus extended-release dipyridamole or clopidogrel, Dr. Gorelick said. Earlier studies of recurrent stroke prevention using aspirin plus extended-release dipyridamole or clopidogrel had relatively few or no African-American subjects, precluding direct comparisons to these other agents. Other large, ongoing studies of clopidogrel vs. aspirin, like MATCH, CHARISMA, and PRoFESS, may provide the necessary data if they include enough African-American subjects.

In the meantime, the higher cost of the thienopyridines may prevent compliance in patients without prepaid prescription plans or in those of lower socioeconomic status. Dr. Sacco recommended that all stroke survivors should receive some form of antithrombotic therapy, and cost should be one factor to consider when making the best choice.

"Ultimately, therapy to prevent recurrent stroke may be geared to what I call macrogenetic therapy," Dr. Arora said. "Rather than giving all patients the same drug across the board, we should tailor drug therapy to each individual's genetic makeup."

"Use of aspirin plus extended-release dipyridamole or clopidogrel for recurrent stroke prevention in African-American ischemic stroke patients will likely be based on physician and patient preference," Dr. Gorelick concluded.

The National Institute of Neurological Disorders and Stroke supported AAASPS through a grant, and Roche Laboratories and Bayer supplied study medications and placebos. Dr. Gorelick receives consultant's and speakers bureau honoraria from Boehringer Ingelheim and Solvay Pharmaceuticals. Dr. Sacco is a consultant and is on the speakers board for Boehringer Ingelheim, Sanofi-Synthelabo, and Bristol-Myers Squibb. Dr. Arora reports no pertinent financial disclosures.

JAMA. 2003;289:2947-2957, 3005-3007

Reviewed by Gary D. Vogin, MD

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