Background disparities in health and health care
US blacks have had a survival disadvantage for some time. Recent data from the National Center of Health Statistics show that a child born in the United States in 2005 can expect to live to almost 78 years of age [84]. The increase in life expectancy repre- sents an improvement from 1955 when the statistic was 69.6 years and from 1995 when it was 75.8 years. Life expectancy for the black population has increased over time; however, in 2005 it was only 73.2 years, about 5 years behind the white popula- tion. Overall, the black–white life expectancy gap in the United States widened during the 1980s but has declined more recently due to relative mortality
improvements in homicide, HIV, unintentional injuries, and, among women, heart disease [85].
Explanations for disparities in life expectancy and stroke risk in US blacks have been linked to higher prevalence of risk factors, greater severity or sensi- tivity to risk factors, and lack of access to medical care [1]. Whereas behavioral and psychosocial factors remain important in conferring risk of disease, new avenues of study such as genomics and proteomics are being explored. Results of a recently published study utilizing NHANES 1999–2002 con- tinues to show that US blacks have a higher preva- lence of blood pressure exceeding 140/90 mm Hg than other racial and ethnic subgroups and that treated blacks and Mexican-Americans have the lowest rates of blood pressure control [86]. Severity or sensitivity to risk factors may also play a role in conferring risk. Such mechanisms, however, are less well understood. For example, some blacks may have a propensity for salt sensitivity and a volume- type hypertension, which is hypothesized to have deleterious effects in certain vascular beds including the brain.
Black patients have generally had less access to medical care as refl ected in the distribution of health insurance, the discrimination against minorities, and the utilization of procedures, treatments, and surgery [1]. Blacks are less likely to have private medical insurance, and a recent study shows that compared with privately insured patients, uninsured patients have higher levels of neurological impair- ment, longer average length of hospital stay, and higher mortality risk for stroke [87]. In another example in relation to access to care, US blacks with acute myocardial infarction continue to be less likely to receive coronary revascularization intervention whether they are admitted to hospitals with or without such services [88]. Even in medical care systems that provide a more universal type of access to care, blacks may be less likely to have cerebral angiography and carotid endarterectomy [89]. This raises the questions as to whether such patients are risk aversive and why this may be the case. There has been a long history of mistrust of the medical care system in the black community, which could cer- tainly be an important factor in risk-aversive behav- ior [90]. The Society of General Internal Medicine Health Disparities Task Force has recommended comprehensive education of healthcare providers
and administrators geared toward better under- standing of racial and ethnic disparities in health and health care as a possible solution to help bridge gaps in minority health care [91].
We now discuss novel stroke clinical trials tar- geted to the African-American community. These studies have helped to shape our modern approach to stroke prevention and treatment in the US blacks.
AAASPS
AAASPS was a recurrent stroke prevention clinical trial targeted to African-American patients [2]. The study design included provisions to engage the com- munity in development, recruitment, safety moni- toring, and dissemination of information in relation to the study [92]. In addition, AAASPS serves as a model for recruitment and retention of minority study subjects who traditionally have been under- represented in clinical trials [90,93,94].
AAASPS was a landmark National Institute of Neurological Disorder and Stroke/NIH-funded double-masked, randomized, controlled clinical trial, which was designed to assess the effi cacy and safety of aspirin and ticlopidine to prevent recurrent stroke among African-American noncardioembolic ischemic stroke patients [2]. A main study tenet was the establishment of grassroots community support and conceptual acceptance of the potential impor- tance of such a trial during the pretrial planning phase, and community involvement during the main fi eld phases to assure adequate recruitment and retention of study subjects [92]. How were we able to successfully recruit and retain over 1,800 African-American stroke patients from over 60 aca- demic and community hospitals across the United States? A key component of the study design was careful preplanning to meet the needs of the African- American community during each phase of the trial.
We carried out surveys to better understand African- American sensitivities in relation to the medical care system, given the legacy of past healthcare abuses that were incurred by this community [90,93]. These types of studies led to the identifi cation of barriers to entry into clinical trials, such as lack of awareness of trials, mistrust, economic factors, and basic com- munication issues (Table 10.3). When we identifi ed such barriers, steps were taken to systematically resolve them across all of the study sites. Cultural
sensitivity training programs were developed and carried out by the AAASPS management staff and shared with the local study staff at the site investiga- tor meetings. Local study staff were educated about the importance of spending adequate time and developing a trustful relationship with potential study participants, and serving as their study advo- cates. Furthermore, the involvement of a study staff from the African-American community was recom- mended, as was the development of an overall study community advisory panel for the main study man- agement site. The same concept was to be embraced locally as satellite community advisory panels were encouraged at local study sites. Attempts to enhance community awareness were achieved by a commu- nity service coordinator, Internet postings about the study, involvement of church healthcare coordina- tors, a community volunteer corps to promote the study, involvement of minority health professionals to identify potential study subjects, a speaker’s bureau, and the use of the media. Church support was sought as was the recognition of the study by major black legislative groups [94].
We also developed a recruitment and retention triangle model, which consisted of three arms: the study patient, his or her family members, and the study subject’s healthcare professionals [93]. Con- ceptually, if any one of the components of the tri- angle weakened, recruitment and retention could be endangered. We emphasized engagement and com- munication with the patient, family members, and the patient’s community physician and healthcare team in an attempt to strengthen study recruitment and retention.
We showed that by careful pretrial planning and thoughtful study measures, our research team could successfully recruit and retain minority subjects in a large-scale, national, clinical trial by breaking down study barriers and being culturally sensitive.
Although we were convinced based on the prelimi- nary trial data from the Ticlopidine Aspirin Stroke
Study (TASS) that ticlopidine would be safe and substantially more effective than aspirin for recur- rent stroke prevention in African-Americans, an effi cacy advantage of ticlopidine over aspirin therapy was not found [2]. In fact, the study was stopped early by the NIH-appointed Data and Safety Moni- toring Board for reasons of futility, and we could not support the use of ticlopidine for stroke prevention in African-Americans. Had the study been contin- ued, there was a 40–50% likelihood that aspirin would be more effi cacious than ticlopidine for recurrent stroke prevention. The AAASPS effi cacy fi ndings are a reminder that subgroup and other nonprimary analyses (e.g., from TASS in this case) may be useful for hypothesis generation but not nec- essarily for making patient management decisions as there may be uncontrolled confounding in such analyses [95,96]. The safety profi le of the two study interventions was similar [2]. Key effi cacy and safety fi ndings from AAASPS are listed in Table 10.4.
Table 10.3 Key barriers to entry into clinical trials as identifi ed in the African-American Antiplatelet Stroke Prevention Study [90]
1 Lack of awareness of clinical trials 2 Mistrust of the medical care system 3 Economic disadvantages
4 Social isolation and communication challenges
Table 10.4 Key effi cacy and safety fi ndings from the African- American Antiplatelet Stroke Prevention Study [2]
Effi cacy
1 Primary outcome end point of recurrent stroke, myocardial infarction, or vascular death: reached by 14.7% of ticlopidine patients (n = 902) and 12.3% of aspirin patients (n = 907) for a hazard ratio = 1.22 (95% confi dence interval: 0.94, 1.57).
2 Secondary outcome of fatal or nonfatal stroke approached a statistically signifi cant reduction favoring aspirin over ticlopidine, P = 0.08.
3 Nine myocardial infarctions and 18 vascular deaths occurred in the ticlopidine treatment group versus eight myocardial infarctions and 18 vascular deaths in the aspirin treatment, none of which was statistically signifi cant.
Safety
1 Laboratory-determined serious neutropenia occurred in 3.4%
ticlopidine-treated patients versus 2.2% aspirin-treated patients (P = 0.12) and 0.3% versus 0.2%, respectively, for thrombocytopenia (P = 0.69).
2 There was one possible case of ticlopidine-induced thrombotic thrombocytopenia purpura.
3 Other serious adverse events did not differ signifi cantly between treatment groups.
4 For study subjects prematurely discontinuing the blind phase of the intervention, rash was more common in the ticlopidine versus aspirin groups (1.7% vs. 0.6%; P = 0.02).
Sickle disease trials in stroke
The Stroke Prevention Trial in Sickle Cell Anemia (STOP) was another landmark study funded by the NIH and conducted in the United States and Canada during the time period 1995–2000 [97–100]. Close to 2,000 children or young adults aged 2–16 years were screened using TCD, and those with two TCD ultrasounds showing middle cerebral artery or inter- nal carotid artery velocity of ≥200 cm/s could be randomized. The trial was halted prematurely when it became apparent that 11 of 67 subjects random- ized to standard treatment (episodic transfusions for symptoms such as pain) had stroke compared with only one study subject in the long-term transfusion group. Therefore, with regular transfusion there was a more than 90% reduction in stroke over and above the 10% per year stroke risk in the other treatment group [100].
STOP II was then designed to determine whether transfusion could be safely withdrawn [99]. About 53% of the STOP subjects undergoing transfusion had their TCD ultrasound velocities revert to lower risk levels (e.g., <170 cm/s). Conceptually, STOP II was designed to enroll 100 children who had high- risk TCD velocities that had reverted to <170 cm/s after at least 30 months of transfusion and MRA did not show higher grades of stenosis or occlusion. Half of the subjects would have continuation of transfu- sion, and half would have transfusion discontinued [100]. Again, the study was stopped early when it was noted that there was rapid reversion of TCD velocities to higher risk levels in those who had stopped transfusion therapy. There were two strokes in the latter group.
Other studies including one testing screening approaches in children with sickle-cell disease and one testing hydroxyurea with transfusion for sec-
ondary stroke prevention are ongoing [99]. Long- term transfusion therapy may pose a risk of iron load, which has become easier to treat with the avail- ability of an oral iron chelator agent. Recommenda- tions from current guideline statements for the management of children with sickle-cell disease are listed in Table 10.5 [101,102].
References available online at www.wiley.com/go/
strokeguidelines.
Table 10.5 Stroke prevention in children with sickle-cell disease: American Heart Association/American Stroke Association Guideline Recommendations [100,101]
1 Screen children with sickle-cell disease with TCD starting at age 2 years.
2 Consider transfusion therapy for those with elevated stroke risk.
3 Continued TCD is recommended for younger children and those with TCD velocities in the conditional range to detect high-risk TCD indications for intervention.
4 Pending additional study, it is reasonable to continue transfusion therapy even if TCD velocities revert to normal.
5 Adults with sickle-cell disease should be screened for cardiovascular risk factors and managed according to general guidelines.
6 Adults with sickle-cell disease and ischemic stroke or TIA should receive general treatment recommendations for control of risk factors and use of antiplatelet agents. Regular transfusion therapy should be considered to reduce hemoglobin S to <30 to 50% of total hemoglobin as should hydroxyurea or extracranial to intracranial bypass surgery when there is advanced occlusive brain disease.
TIA, transient ischemic attack; TCD, transcranial Doppler.