- Email: [email protected]
Why women are not small men
Maturitas xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Editorial
Why women are not small men
When one meets a person in everyday life, it is immediately evident if this person is a man or a woman, at least in the majority of cases. On the one hand this conclusion is based on biological characteristics such as body shape and on the other hand on gender specific features, for example clothing, hairstyle or ornamentation which are culturally defined. Of course there are cases where it takes more than the usual split second, but these are and will remain an exception. Therefore it seems ridiculous to explain to somebody, let alone someone with an academic education, that there are certain differences between women are men. However, astonishingly enough those same people, who for most of the time know perfectly that women and men are not similar, can erase this basic knowledge when they are doing research. In medical science it has been accepted that differences between men and women can be completely disregarded. Even worse, for a long time the mere existence of women has been ignored. Caucasian men, preferably with a height of 180 cm and weight of 70 kg, were the standard. Women were being reduced to a small type of men. In 1989 a key publication of the Physicians Health study showed that aspirin use was associated with a reduction of heart disease, but the abstract fails to mention that this study was performed exclusively in men [1]. Only in the discussion the authors mention that “there is no direct evidence of the role of aspirin in the cardiovascular prevention of women”. Twenty years later it was found that aspirin did not lower the incidence of myocardial infarction in women, although it did reduce the incidence in stroke [2]. Since then lessons have been learned about the hazard of not paying attention to sex differences in medical research. Major health governmental institutes such as the Food and Drug Administration (FDA) have statements and regulations which acknowledge the importance of establishing research results for women separately instead of mere extrapolating results found in men [3]. It is undeniable that progress has been made and that sex- and gender-specific research has been mainstreamed more and more. However despite all these measures, the number of women participating in major trials which were presented at the recent European Society of Cardiology conference august 2017 was disappointingly low. Three of the most influential trials presented were the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) and Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification (REVEAL) trial [4–6]. The CANTOS trial was spectacular because it proved that reducing inflammation by canakinumab, an interleukin-1β monoclonal antibody, led to a reduced risk of cardiovascular disease. Of the 10,061 patients who were randomized only 25,6% were women [4]. No sex-specific analysis was presented in the main publication. The COMPASS study randomized 22,395 patients with stable coronary artery disease to rivaroxaban, rivaroxaban and aspirin or aspirin only, included even less women; only 22% [5]. A sub-analysis showed that the combination of rivaroxaban reduced cardiovascular disease in both men and women. Notably, a supplementary table in the appendix a subgroup analysis showed that women compared to men showed a trend of more major bleeding with rivaroxaban and aspirin compared to aspirin alone. It would be very interesting to perform a netclinical benefit analysis because this could potentially show relevant sex differences. Lastly, the REVEAL trial compared anacetrapib or placebo on addition of background intensive lipid lowering therapy in an imposing 30,449 patients with atherosclerotic disease managed only to randomize 16.1% women [6]. In the supplementary material a subgroup analysis showed that the effect of anacetrapib to lower cardiovascular events was significant only in men. Although in women and men the rate ratio of the effect of anacetrapib compared to placebo was comparable, the outcome was not significant due to insufficient power in women (RR 0.93 (95% Confidence Interval(CI) 0.78–1.11) vs RR 0.90 (95%CI 0.84–0.97)). Is the insufficient number of women randomized to clinical trials a problem? The answer is affirmative. An analysis of ten prescription drugs that were withdrawn from the US the market between 1997 and 2001 found that eight posed “greater health risks for women”, mainly because of adverse drug events due to known pharmacodynamic differences (e.g.: five drugs were withdrawn due to risk of torsades de pointes in women) [7]. Therefore it is important that starting from pre-clinical phases onwards efforts have to be made to make sure a sufficient number of female participants are enrolled to be able to make relevant sex-specific analysis. The problem has been identified by amongst others FDA, National Institute of Health (NIH) and the National Institute on Drug Abuse Clinical Treatment Clinical Trials Network (NIDA-CCTN) which have created tools for clinical trialists with specific recommendations how to include more women in trials for example by offering childcare and post bulletin board advertisements in beauty salons and laundromats. However, the above mentioned trials have shown that despite all good intentions, the number of women has not increased. A detailed analysis at which stage of the process women dropout and for which reason is necessary to make a masterplan to truly improve this state of affairs. Although sex-specific sub-analyses have become more and more standard, these will are not really meaningful unless a sufficient number of women are included. Until then women will remain “a subclass of small men”.
http://dx.doi.org/10.1016/j.maturitas.2017.09.008
0378-5122/ © 2017 Published by Elsevier Ireland Ltd.
Maturitas xxx (xxxx) xxx–xxx
Editorial
Contributor Jeanine Roeters van Lennep is the sole author. Conflict of interest None declared. Funding None. Provenance and peer review Commissioned, not peer reviewed. References [1] Steering Committee of the Physicians’ Health Study Research G, Final report on the aspirin component of the ongoing physicians’ health study, N. Engl. J. Med. 321 (3) (1989) 129–135. [2] C. Antithrombotic Trialists, C. Baigent, L. Blackwell, R. Collins, J. Emberson, J. Godwin, et al., Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials, Lancet 373 (9678) (2009) 1849–1860. [3] Investigational new drug applications amendment to clinical hold regulations for products intended for life-threatening diseases and conditions. Food and drug administration, HHS. Final rule, Fed. Regist. 65 (106) (2000) 34963–34971. [4] P.M. Ridker, B.M. Everett, T. Thuren, J.G. MacFadyen, W.H. Chang, C. Ballantyne, et al., Antiinflammatory therapy with canakinumab for atherosclerotic disease, N. Engl. J. Med. 377 (12) (2017) 1119–1131. [5] J.W. Eikelboom, S.J. Connolly, J. Bosch, G.R. Dagenais, R.G. Hart, O. Shestakovska, et al., Rivaroxaban with or without aspirin in stable cardiovascular disease, N. Engl. J. Med. (2017). [6] M.J. Landray, G. Reveal Collaborative, L. Bowman, FCESJCHKWWSEV-MSWCPCEBRC. Randomized evaluation of the effects of anacetrapib through lipid-modification (REVEAL)-A large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: trial design, recruitment, and baseline characteristics, Am. Heart J. 187 (2017) 182–190. [7] General Accounting Office. Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women. 2001 Jan 19. GAO-01-286R, (2001).
Jeanine E. Roeters van Lennep Department of Internal Medicine, Division Vascular Medicine, Erasmus MC, 's-Gravendijkwal 230, 3015 CE, Postbus 2010, 3000 CA, Rotterdam Room: D-425, Rotterdam, The Netherlands E-mail address: [email protected]
2
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Editorial
Why women are not small men
When one meets a person in everyday life, it is immediately evident if this person is a man or a woman, at least in the majority of cases. On the one hand this conclusion is based on biological characteristics such as body shape and on the other hand on gender specific features, for example clothing, hairstyle or ornamentation which are culturally defined. Of course there are cases where it takes more than the usual split second, but these are and will remain an exception. Therefore it seems ridiculous to explain to somebody, let alone someone with an academic education, that there are certain differences between women are men. However, astonishingly enough those same people, who for most of the time know perfectly that women and men are not similar, can erase this basic knowledge when they are doing research. In medical science it has been accepted that differences between men and women can be completely disregarded. Even worse, for a long time the mere existence of women has been ignored. Caucasian men, preferably with a height of 180 cm and weight of 70 kg, were the standard. Women were being reduced to a small type of men. In 1989 a key publication of the Physicians Health study showed that aspirin use was associated with a reduction of heart disease, but the abstract fails to mention that this study was performed exclusively in men [1]. Only in the discussion the authors mention that “there is no direct evidence of the role of aspirin in the cardiovascular prevention of women”. Twenty years later it was found that aspirin did not lower the incidence of myocardial infarction in women, although it did reduce the incidence in stroke [2]. Since then lessons have been learned about the hazard of not paying attention to sex differences in medical research. Major health governmental institutes such as the Food and Drug Administration (FDA) have statements and regulations which acknowledge the importance of establishing research results for women separately instead of mere extrapolating results found in men [3]. It is undeniable that progress has been made and that sex- and gender-specific research has been mainstreamed more and more. However despite all these measures, the number of women participating in major trials which were presented at the recent European Society of Cardiology conference august 2017 was disappointingly low. Three of the most influential trials presented were the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) and Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification (REVEAL) trial [4–6]. The CANTOS trial was spectacular because it proved that reducing inflammation by canakinumab, an interleukin-1β monoclonal antibody, led to a reduced risk of cardiovascular disease. Of the 10,061 patients who were randomized only 25,6% were women [4]. No sex-specific analysis was presented in the main publication. The COMPASS study randomized 22,395 patients with stable coronary artery disease to rivaroxaban, rivaroxaban and aspirin or aspirin only, included even less women; only 22% [5]. A sub-analysis showed that the combination of rivaroxaban reduced cardiovascular disease in both men and women. Notably, a supplementary table in the appendix a subgroup analysis showed that women compared to men showed a trend of more major bleeding with rivaroxaban and aspirin compared to aspirin alone. It would be very interesting to perform a netclinical benefit analysis because this could potentially show relevant sex differences. Lastly, the REVEAL trial compared anacetrapib or placebo on addition of background intensive lipid lowering therapy in an imposing 30,449 patients with atherosclerotic disease managed only to randomize 16.1% women [6]. In the supplementary material a subgroup analysis showed that the effect of anacetrapib to lower cardiovascular events was significant only in men. Although in women and men the rate ratio of the effect of anacetrapib compared to placebo was comparable, the outcome was not significant due to insufficient power in women (RR 0.93 (95% Confidence Interval(CI) 0.78–1.11) vs RR 0.90 (95%CI 0.84–0.97)). Is the insufficient number of women randomized to clinical trials a problem? The answer is affirmative. An analysis of ten prescription drugs that were withdrawn from the US the market between 1997 and 2001 found that eight posed “greater health risks for women”, mainly because of adverse drug events due to known pharmacodynamic differences (e.g.: five drugs were withdrawn due to risk of torsades de pointes in women) [7]. Therefore it is important that starting from pre-clinical phases onwards efforts have to be made to make sure a sufficient number of female participants are enrolled to be able to make relevant sex-specific analysis. The problem has been identified by amongst others FDA, National Institute of Health (NIH) and the National Institute on Drug Abuse Clinical Treatment Clinical Trials Network (NIDA-CCTN) which have created tools for clinical trialists with specific recommendations how to include more women in trials for example by offering childcare and post bulletin board advertisements in beauty salons and laundromats. However, the above mentioned trials have shown that despite all good intentions, the number of women has not increased. A detailed analysis at which stage of the process women dropout and for which reason is necessary to make a masterplan to truly improve this state of affairs. Although sex-specific sub-analyses have become more and more standard, these will are not really meaningful unless a sufficient number of women are included. Until then women will remain “a subclass of small men”.
http://dx.doi.org/10.1016/j.maturitas.2017.09.008
0378-5122/ © 2017 Published by Elsevier Ireland Ltd.
Maturitas xxx (xxxx) xxx–xxx
Editorial
Contributor Jeanine Roeters van Lennep is the sole author. Conflict of interest None declared. Funding None. Provenance and peer review Commissioned, not peer reviewed. References [1] Steering Committee of the Physicians’ Health Study Research G, Final report on the aspirin component of the ongoing physicians’ health study, N. Engl. J. Med. 321 (3) (1989) 129–135. [2] C. Antithrombotic Trialists, C. Baigent, L. Blackwell, R. Collins, J. Emberson, J. Godwin, et al., Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials, Lancet 373 (9678) (2009) 1849–1860. [3] Investigational new drug applications amendment to clinical hold regulations for products intended for life-threatening diseases and conditions. Food and drug administration, HHS. Final rule, Fed. Regist. 65 (106) (2000) 34963–34971. [4] P.M. Ridker, B.M. Everett, T. Thuren, J.G. MacFadyen, W.H. Chang, C. Ballantyne, et al., Antiinflammatory therapy with canakinumab for atherosclerotic disease, N. Engl. J. Med. 377 (12) (2017) 1119–1131. [5] J.W. Eikelboom, S.J. Connolly, J. Bosch, G.R. Dagenais, R.G. Hart, O. Shestakovska, et al., Rivaroxaban with or without aspirin in stable cardiovascular disease, N. Engl. J. Med. (2017). [6] M.J. Landray, G. Reveal Collaborative, L. Bowman, FCESJCHKWWSEV-MSWCPCEBRC. Randomized evaluation of the effects of anacetrapib through lipid-modification (REVEAL)-A large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: trial design, recruitment, and baseline characteristics, Am. Heart J. 187 (2017) 182–190. [7] General Accounting Office. Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women. 2001 Jan 19. GAO-01-286R, (2001).
Jeanine E. Roeters van Lennep Department of Internal Medicine, Division Vascular Medicine, Erasmus MC, 's-Gravendijkwal 230, 3015 CE, Postbus 2010, 3000 CA, Rotterdam Room: D-425, Rotterdam, The Netherlands E-mail address: [email protected]
2