In this systematic review, reporting of older patients and ethnic/racial
minorities was poor with <20% of the included RCTs mentioning
these demographic subsets.
Enrollment of women and American Indian/Alaskan natives in RCTs of AF
matched their demographic share of disease burden. Hispanics and Asians
were
over-represented and Blacks, native Hawaiian or Pacific Islander and
non-Whites were under-represented in RCTs compared with real world data.
Representation of women was significantly higher in industry or academic
center sponsored RCTs compared with government funded RCTs. Mean age of
participants was less than the corresponding weighted mean age in the
comparative epidemiological data, and varied significantly based on
location, funding sources, baseline population and according to
management strategies used for prevention of stroke or treatment of AF.
The 1993 National Institute of Health Revitalization act legally
required RCTs to include men and women consistent with the known sex
related prevalence of the disease under study. More recently, the
Government Accountability Office (GAO) issued a follow-up report calling
for improved reporting of women’s enrollment in RCTs29.
Since RCTs are regarded as the ”gold standard” for shaping up the
management strategies and guidelines, inclusion of women and demographic
subgroups sustain the generalizability of the findings to the population
as a whole and allows subgroup analyses to determine influence of
different ethnicities. The current findings are in line with recent
review by Scott and colleagues who also reported adequate representation
of women in the RCTs that supported FDA approval of cardiovascular drugs15. However, women with AF were reported to have lower
quality of life, higher risk of ischemic stroke and higher mortality as
compared to men 5-7. Therefore, such complexity of AF
in women endorses the need for adequate enrollment in future RCTs as
well. Our finding of lower proportion of women in government funded RCTs
needs attention in this regard. The FDA guidelines in 1977 called for
exclusion of women of childbearing potential from early phases of RCTs.
Even
though, such policies have been revised since that time, it is still
plausible that this may have deterred female recruitment in RCTs
especially the ones sponsored by the Government agencies30. Additionally, lack of awareness about RCTs and
logistical barriers might also have contributed to the lower enrollment
rates.
Co-morbidities leading to AF vary based on age, sex and ethnicities31, 32. The prevalence of AF rises
steadily with age, and Blacks have a 2-5 times higher risk of
AF-associated stroke than Whites. However, the enrollment of older
patients was reported in only 18.7% of the included RCTs. Similarly,
only 12.7% RCTs reported ethnic/racial population, out of which Black
patients made up disappointingly <2% of cohorts. In order to
improve enrollment of these groups, following strategies can be
considered. First, greater cultural sensitivity is needed to ensure
adequate recruitment and consent procedures that are consistent with
different ethnic/racial cultures 33. Second, targeting
inner city population that are likely to have a high minority ethnic
population and hiring special advocacy workers to provide a bridge
between recruiters and minority population 34. Third,
addressing the obstacles for women participation such as offering
childcare or transportation, having special considerations when
enrolling fertile women, and ensuring they have access to counseling and
medical care 35. Fourth, an Office of Geriatric Health
and Aging can be created to review protocols and enrollment of older
population similar to the workings of Office of Women’s Health which was
established by Congressional mandate in 1994 32.
Fifth, simplifying consent forms, adding time to consult with family,
the use of proxy data or remote follow up can be elicited to overcome
barriers to participation of underrepresented demographics in RCTs32.
Our study has certain limitations. Since we did not have access to
individual participant’s data, this review was limited to trial-level
information. We relied on published trials and thus risk of publication
bias cannot be ignored. Overall, there was inadequate reporting of older
patients and ethnic/racial minorities in AF RCTs. The representation of
racial demographics did not start until 2007 in AF RCTs with reporting
on certain races such as Native Hawaiian or Pacific Islanders beginning
in 2011. This limit inferring strong conclusion around such racial
demographics. Furthermore, some RCTs have only reported race as White or
non-White which makes detailed analysis of non-White racial groups
impossible from those studies. Additionally, one can argue that
treatments in RCTs are examined to determine effects in population at
risk, and naturally stroke prevention trials would reflect older cohorts
given higher inherent risk of stroke compared with younger participants
in catheter ablation trials.
In conclusion, this systematic review suggests adequate
enrollment of women, older patients and American Indian/Alaskan natives,
over recruitment of Hispanics and Asians and under recruitment of
Blacks, non-Whites and native Hawaiian or Pacific Islanders in Trials of
AF compared with their demographic share of disease burden.
These data demand a diligent review of the policies by organizations and
investigators to ensure adequate representation of these demographic
subgroups in future RCTs.