Under-representation of elderly and women in clinical trials
Introduction
Despite the enormous decline in the burden of cardiovascular diseases (CVDs) during the past decades, mainly due to improvements in primary and secondary prevention and to the improved survival during acute coronary events, CVD remains the main cause of death and disability in both sexes and in particular in elderly people, commonly defined > 65 years old [1]. Furthermore, in the past decades a gender shift in the epidemiology of CVD has also been observed as consequence of the progressive increase of the population of postmenopausal females. This change in the size of the population of postmenopausal females has had significant implications on the incidence of CVD, as risk factors like arterial hypertension, type 2 diabetes and dyslipidaemia are strictly correlated with the state of oestrogen deficiency and the menopausal status [2], [3]. For decades, CVD has been considered a predominantly male disease, and the misperception that females are protected against CVD, and that cancer is their major cause of death was mounted mainly by campaigns on breast cancer sensibilisation [4]. However, more recently, given the increasing prevalence of CVD in women, the sex and gender aspects in the burden of CVD in general, and in particular the differences in its pathophysiology, clinical, prognostic and therapeutic aspects have become clearer.
Despite these improvements, elderly and women are still often under-represented in cardiovascular randomised clinical trials (RCTs). This implies that current recommendations for the management of CVD are not adequately devised for elderly and women. Aim of this review is to critically analyse the topic of under-representation of elderly and women in cardiovascular RCTs.
Section snippets
General considerations on clinical trials in cardiology
RCTs are generally accepted as the most unbiased measures of effectiveness and safety for new cardiovascular drugs [8]. The results of well-conducted RCTs provide clinicians and health policy makers with the evidence-based data on the best available treatment for patients and are used to formulate the international guidelines that support the therapeutic decisions of clinicians.
In order to obtain evidence-based results, applicable and generalizable to the affected population of the daily
Elderly and women in cardiovascular trials
Differences in CVD pathophysiologies, risk factors and co-morbidities, as well as in pharmacodynamics and pharmacokinetics, exist between men and women as well as between young and elderly, and are relevant issues for the management of CVD. Unfortunately, most treatments have been tested primarily in middle-aged men [5], while the results are erroneously translated to young individuals and women. Of note, women tend to have different response to treatments in different periods of their lives,
Women and cardiovascular drugs
In these past decades increasing evidence has demonstrated sex-gender differences in the action of cardiovascular drugs. The many biological differences that exist between the sexes, from basic research to responses on medical therapies, are important within the whole range of CVD and translate into socio-cultural behavioural differences (‘gender’) between men and women [13].
Specific pathways where biological (‘sex’) differences have been shown to be of importance include myocardial calcium
Elderly and cardiovascular trials
The definition of elderly patients is, today, based only on the chronological age [1], [22] (Table 3) but it is now clear that age thresholds are arbitrary and non informative for the purpose of delineating constructive clinical guidance on treatment decisions. Indeed, elderly are a heterogeneous population in which the chronological age is not able to reflect all the variables, both disease- and non disease-related, that are responsible of different elderly phenotypes and response to
Comorbidities and poly-pharmacy in the elderly
Elderly are the main users of medications and also those most frequently exposed to adverse drug reactions; the lack of available data from RCTs conducted in the elderly limits the availability of adequate information to patients and prescribers, to support safer use of medications. In particular, frail elderly and those with co-morbidities are not included, questioning the external validity and the safety of most treatments. The presence of chronic comorbidities is a growing health problem in
Outcomes and prevention in the elderly
The desirable outcome in the elderly may depend on the presence of frailty and disability status and different patients may rate differently values on benefits and risks. Therefore, in the elderly, most often an effect on a patient related outcome (functional capacity, quality of life) may be more relevant as well as an improvement in survival. Furthermore, some adverse events, such as dizziness, frequent with cardiovascular drugs and often leading to falls, may be of greater importance in the
Generalizability of results to the real-world
The exclusion of elderly people and women from the participation in the randomised intervention studies leads to a large gap between real-world older adults and those who participate in the intervention studies. This gap attempts to extrapolate the results from studies not representative of the real world and the key consequence is that physicians and scientists do not have adequate, evidence-based information to guide the care of elderly and women. Without clear knowledge of effectiveness and
Conclusion
The inadequate inclusion of elderly and women in early RCTs reduces the usefulness of the information provided by trials on efficacy. Too often results have been extrapolated in these two groups of patients from subgroups analysis or have been directly translated from the results obtained in the young male counterparts. Therefore, the risk of adverse events and the real effectiveness and safety of these medications is largely unknown in elderly and women. The participation of populations
Conflict of interest
The authors report no relationships that could be construed as a conflict of interest.
Acknowledgments
None.
References (33)
- et al.
Sex differences in cardiovascular risk factors and disease prevention
Atherosclerosis
(2015 Jul) - et al.
Need for gender-specific pre-analytical testing: the dark side of the moon in laboratory testing
Int. J. Cardiol.
(2015) - et al.
Principles of drug therapy for the elderly patient
Mayo Clin. Proc.
(2003) When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly
Exp. Gerontol.
(2003)Under-representation of the elderly in clinical trials
Eur. J. Intern. Med.
(Oct 2005)Middle Age and Aging
(1968)- et al.
Gender differences in the cardiovascular effect of sex hormones
Nat. Rev. Cardiol.
(2009) The Yentl syndrome
N. Engl. J. Med.
(1991)- et al.
Gender differences in the effect of cardiovascular drugs: a position document of the working group on pharmacology and drug therapy of the ESC
Eur. Heart J.
(2015) - et al.
The 2030 problem: caring for aging baby boomers
Health Serv. Res.
(2002 Aug)
Cardiovascular drug therapy in elderly patients: specific age-related pharmacokinetic, pharmacodynamic and therapeutic considerations
Drugs Aging
Users' guides to the medical literature: XXV. Evidence-based medicine: principles for applying the users' guides to patient care. Evidence-based medicine working group
JAMA
Threats to applicability of randomised trials: exclusions and selective participation
J. Health Serv. Res. Policy
To whom do the research findings apply?
Heart
Evaluation of large scale clinical trials and their application to usual practice
Heart
The causes and effects of socio-demographic exclusions from clinical trials
Health Technol. Assess.
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