Diversity is richness: why data reporting according to sex, age, and ethnicity matters

Traditionally, data have been reported for the entire patient population of a given study, registry or trial. If subgroups have been further investigated, they typically involved comorbidities such a hypertension, diabetes among others and were often not predefined. Only more recently are data in many, but not all studies, presented not only for comorbidities but also for males and females separately in a predefined manner, while ethnicity is rarely separately presented or analysed,¹ although clinical presentation, treatment effects and outcomes may differ in many respects.

Diversity as a reality

While in oncology certain tumours are long known to primarily affect males or females, up until recently sex differences where less obvious in cardiology. Indeed, for decades, heart disease was considered a male disease and the male heart was the human heart for many, although evidence accumulated that sex matters for cardiac conditions. Furthermore, given modern longevity, age became an important further aspect of patient diversity. Indeed, in Western societies up to 20% of the population are older than 65 years with longevity increasing further.² Finally, ethnicity is often overlooked, which is an increasing concern in today’s global world, relative to differences in conditions and care.

Sex and gender

Initiatives to incorporate sex as a biological variable into research design and publication began in 2001 with the landmark publication by the Institute of Medicine, now the National Academy of Medicine, ‘Does Sex Matter?’³ The overarching conclusion of that publication was that biological sex influences health and disease from ‘womb to tomb’.

The Institute also clarified that in the English language sex should refer to the biological and gender to the cultural aspects of humans. Indeed, both biological (genetics and epigenetics) and cultural (lifestyle) aspects may affect, disease presentation, response to treatments, and natural history. Of note, sex is a biological variable defined by the genetic karyotype (XX vs. XY) that determines metabolism in cells, tissue, and organs. Thus, differences in biological and physiological measures, including cellular and molecular pathways,⁴ should be referred to as ‘sex-differences’ in humans and described for females and males separately. Gender, on the other hand, refers to the social, environmental, cultural, and behaviour factors that influence a person’s self-identity, lifestyle, and health behaviours. Components of a person’s gender will influence health through various activities such as smoking, dietary choices, exercise, and the kind of sports just to mention a few. All of which in turn influences health at various biological levels.

Why sex matters in cardiology

The evidence for sex differences in mechanisms, clinical presentations, and natural history of cardiovascular diseases, as well as the response to medical and interventional treatments of females and males is substantial. Indeed, males and female hearts differ not only in size and structure but also in mechanisms, presentation, and outcomes of heart disease.

For instance, women tend to develop chronic heart failure at a more advanced age, present more often with heart failure with preserved,⁵ rather than reduced ejection fraction,^{5  ,  6} are more symptomatic and have a worse quality of life than men but also a better prognosis.⁶ In addition, in women, heart failure has more commonly a non-ischaemic aetiology with arterial hypertension and diabetes mellitus as leading comorbidities.

On the other hand, men have more frequently obstructive coronary, cerebrovascular, and peripheral vascular disease, particularly among younger age groups, while females more often suffer from ischaemia with no-obstructive coronary artery disease, a condition related to microvascular rather than epicardial coronary artery dysfunction.^{7  ,  8} As a consequence, women with chest pain are more likely to have normal coronary arteries on computed coronary angiography.⁹ However, if they have obstructive coronary artery disease they do experience a higher rate of major cardiac events after percutaneous coronary interventions.¹⁰

Sex differences have been observed in atrial fibrillation including epidemiology (lower prevalence in women, older age at presentation), pathophysiology (triggers and substrate),¹¹ clinical presentation (women are more likely to be symptomatic), natural history,^{12  ,  13} and treatment (women more often receive medical treatment rather than ablation compared to men¹⁴ and if they undergo the procedures have higher rates of complications).¹⁵ Sex differences are observed for stroke and embolism as well. For example, in the ARISTOTLE trial, women had a similar rate of stroke or systemic embolism, but a lower risk of mortality and less clinically relevant bleeding than men did.¹⁶ However, the efficacy and safety benefits of apixaban compared with warfarin were consistent in men and women.¹⁷

Sex differences are well-documented in the response to drugs. Indeed, women and men differ in body weight that can affect drug pharmacodynamics¹⁸ as well as body composition (greater body fat composition in women) and physiology (hormonal influences during the menstrual cycle, menopause, and pregnancy) and they also differ in drug pharmacokinetics (absorption, distribution, metabolism, and excretion), so that it is not rare that women may respond differently to cardiovascular drugs compared to men.¹⁹ While in primary prevention, overall the protective effects of aspirin have been challenged recently, a trial focusing on sex-specific effects of the antiplatelet drug in women showed a reduction in the risk of ischaemic stroke, without an increase in haemorrhagic stroke nor a significant effect on myocardial infarction, cardiovascular, and all-cause mortality.²⁰ Yet, the most recent meta-analysis on aspirin unfortunately did not report data based on sex.²¹

In the setting of acute coronary syndromes, women present more often with atypical symptoms,²² have a higher risk of major bleeding than men not only in this context²³ but also after venous thromboembolism when treated with novel oral anticoagulants.²⁴ Analyses of large trials and registry data suggest that male and female acute coronary syndrome patients experience similar benefits from antithrombotic therapy without significant difference in treatment utilization rates, yet women are consistently at higher risk of bleeding than men²⁵ potentially due to their smaller body size, older age at presentation, reduced creatinine clearance, higher prevalence of comorbidities such hypertension, diabetes, and renal dysfunction. Furthermore, acute cardiac conditions among females may have different underlying causes such as the Takotsubo syndrome (95% postmenopausal women^{26  ,  27}) or spontaneous coronary artery dissection that affects preferentially women in the child bearing age.^{28  ,  29}

Also, women tend to be undertreated when diagnosed with coronary artery disease. For instance, they are less likely to receive than males.³⁰ Furthermore, in some,²² but not other studies,³¹ women were less likely to receive guideline-based treatment for acute coronary syndromes, although the guidelines were not developed based on evidence for males and females independently. Finally, women exhibit higher rates of adverse reactions to antiarrhythmic drugs, especially those that prolong the QT-interval than men due baseline prolonged repolarization. Thus, care should be taken in the use of QT-prolonging drugs in women.³²

Sex distribution and outcomes of studies

It is, therefore, obvious that the sex distribution of populations enrolled into studies, registries or trials will affect the results and eventually guideline recommendations based on these results. Thus, reporting data not only overall but also separately according to sex (for other aspects of diversity; see below) is scientifically meaningful and clinically important. Indeed, inattention to sex as a biological variable may result in inequities of care. Of note, sex has yet to be considered or incorporated into most guidelines for cardiovascular diseases.^33–38 For these inequities to be addressed, and in order to facilitate development of guidelines that do consider biological and clinical differences of males and females, data for each sex should be presented and made publicly available. Analysis of data by sex, if sufficiently powered, should be pre-defined. Implementation of an editorial policy which requires data from basic and clinical studies to be disaggregated by sex would address this important issue.

The acceptance of such a concept within scientific and medical communities progressed slowly until the European Commission Directorate-General for Research and Innovation in 2003 started ‘questioning systematically whether, and in what sense, sex and gender are relevant in the objectives, methodology and reporting of projects’. Of note, the European Commission reaffirmed this policy in 2014, stating that ‘integrating gender/sex analysis in research and innovation content….helps improve the scientific quality and societal relevance of the produced knowledge, technology and/or innovation’.³⁹ Consistent with these goals and with policies of international high impact Journals and research funding agencies in Europe (European Commission, Dutch Ministry of Health, Wellbeing and Sports, Germany, French National Research Agency, German Research Foundation, Irish Research Council, Research Council of Norway, Spanish Ministry of Science Innovation and Universities, Swedish Research Council, and the UK Research and Innovation),^{39  ,  40} reporting of demographic and outcome data of articles by sex is important.

Age as a confounder

Particularly in ageing societies with the increasing longevity, age has become an important confounder of cardiovascular care. Indeed, elderly patients in general have higher event rates particularly in acute cardiac conditions⁴¹ and increased rates of procedural complications both in male and female patients. Furthermore, pharmacokinetic and pharmacodynamic change with age because body fat and weight and renal function decrease with age, Importantly, bleeding risk with antiplatelet⁴² and in particular anticoagulant drugs⁴³ increases with age—all factors that need to be considered when interpreting data of studies, registries and trials as well as in everyday practice. As a consequence, among European Society of Cardiology Guidelines, that on hypertension have introduced age as a major decision criterion on blood pressure target levels.⁴⁴ However, these guidelines have made this recommendation without regard to potential effects of sex differences. Of note, elderly are frequently undertreated particularly in prevention: although stopping statins in elderly patients is associated with a 30% increase in major adverse cardiovascular events (MACE),⁴⁵ many physicians still consider it unnecessary to prescribe or continue preventive measures in the elderly. Furthermore, age and sex can interact; for instance, in paediatric cancer patients, most studies support the notion that female sex is a significant risk factor for anthracycline-induced cardiotoxicity,⁴⁶ while there is anecdotal evidence that female sex protects against it in adult cancer patients.

Ethnicity

In our global world, patient populations reflect diverse ethnicities, while most diagnostic, preventive and treatment strategies have been developed based on evidence obtained from more homogeneous and predominately Caucasian groups. In addition to differences in genetic background and culture which manifest in different propensity for development conventional risk factors for cardiovascular disease including obesity, hypertension, and diabetes,⁴⁷ societal biases and access to health care may limit participation in clinical trials, lack of ethnic-based outcomes and perpetuate disparities in care.

Thus, although sex differences may be a common denominator for evaluating data, ethnicity should also be considered as important variable in data collection, reporting, and analysis. Indeed, the natural history of cardiovascular disease, the prevalence of MACE in acute coronary syndromes⁴⁸ or heart failure,⁴⁹ the yield of several diagnostic tests as well as the benefit and side effects of medications and interventions differ substantially among ethnicities. For instance, Afro-Americans and native Africans have a much higher prevalence of high blood pressure, in particular malignant hypertension, for which diuretics have greater efficacy than in Caucasians.⁵⁰ Diabetes prevalence varies by ethnicity, with higher rates observed in Southeast Asians,⁵¹ Arabs, Hispanic,⁵² and indigenous populations.⁵³

Data reporting and diversity

The editors of the European Heart Journal agree that adopting a new editorial policy which considers diversity, in particular regarding sex, gender, age, and ethnicity will serve cardiovascular science and eventually patient care. Part of this policy will follow the Guidelines for Sex and Gender Equity in Research (SAGER; Table 1). Indeed, disaggregating data by sex improves transparency and reproducibility of data so that incorrect conclusions due to biological differences between females and males in relation to demographics, mechanisms and presentation of disease and response to treatment can be reduced,⁵⁴ with guidelines becoming much more personalized and appropriate. Similar recommendations as outlined in Table 1 should be used not only for sex but also for age and ethnicity. Reporting data disaggregated by sex, age, and ethnicity depending on the scope and population of given studies will help in identifying differences in clinical presentation, predictive values of diagnostic tests, drug toxicity, and/or clinical outcomes. In addition, this will allow for proper meta-analyses, informed sample size calculations for the design of future studies and trials, and set the basis for the design of studies validating these results.⁵⁴

Table 1.

Recommendation for reporting diversity in papers submitted the European Heart Journal

Parameter	Recommendations
Age	Study inclusion and exclusion according to age should be mentioned in the methods section as should be stratification by age group. In the results section, median values and range should be given.
Sex	This term refers to biological factors and information to this issue should be given in the methods section and data given in the results section for both females and males. If only one sex is investigated, the reason for that should be given.
Gender	This term refers to the cultural and psychosocial aspects. If appropriate this should be defined in the methods section and results given separately in the results section.
Ethnicity	If multi-ethnic populations are studied, the classification should be defined in the methods section and the results given separately in the results section.

To implement the new policy, the European Heart Journal will adopt the definitions of sex and gender proposed by the Institute of Medicine Report,³ the United States National Institutes of Health,⁵⁵ and the Canadian Institutes of Heart Research.  ⁵⁶ Thus, in some situations, it may be appropriate to report both biological sex and current gender identity.³⁹ To assist authors, a general outline for manuscript preparation is included in this editorial (Table 1), in the EHJ Instructions to Authors, and can be found in detail in the Sex and Gender Equity in Research (SAGER) guidelines.⁵⁷ Lack of compliance will not prevent the publication of the manuscript, but it will be disclosed similarly to conflict of interest disclosures. The EHJ will also propose sex-stratified data be uniformly provided (in the work when relevant, in the Appendix or Cloud when not), and codified in the International Committee of Medical Journal Editors (ICMJE) disclosure form.

Conclusion

In summary, diversity matters, be it sex, gender, age, or ethnicity and might become a strength in the management of cardiac patients and if fully acknowledged would be a first step to more tpersonalized medicine. We should seriously consider this diversity when reporting and analysing data of studies, registries, and trials as depending on their distribution within the investigated population that may greatly affect the results and eventually Guideline recommendations.

Conflict of interest: none declared.