Author + information
- Received December 17, 2018
- Accepted December 20, 2018
- Published online February 25, 2019.
- Muthiah Vaduganathan, MD, MPHa,∗,
- Ayman Samman Tahhan, MDb,∗,
- Alaaeddin Alrohaibani, MDb,
- Stephen J. Greene, MDc,
- Gregg C. Fonarow, MDd,
- Orly Vardeny, PharmD, MSe,
- JoAnn Lindenfeld, MDf,
- Mariell Jessup, MDg,
- Mona Fiuzat, PharmDc,
- Christopher M. O’Connor, MDh and
- Javed Butler, MD, MPH, MBAi,∗ ()
- aBrigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, Boston, Massachusetts
- bEmory Clinical Cardiovascular Research Institute, Emory University School of Medicine, Atlanta, Georgia
- cDuke Clinical Research Institute and Division of Cardiology, Duke University Medical Center, Durham, North Carolina
- dAhmanson-UCLA Cardiomyopathy Center, University of California Los Angeles, Los Angeles, California
- eCenter for Care Delivery and Outcomes Research, Minneapolis VA Health Care System and University of Minnesota, Minneapolis, Minnesota
- fVanderbilt Heart and Vascular Institute, Nashville, Tennessee
- gAmerican Heart Association, Dallas, Texas
- hInova Heart and Vascular Institute, Falls Church, Virginia
- iDepartment of Medicine, University of Mississippi, Jackson, Mississippi
- ↵∗Address for correspondence:
Dr. Javed Butler, Department of Medicine (L650), University of Mississippi, 2500 North State Street, Jackson, Mississippi 39216.
More women than men currently live with heart failure (HF) in the United States (1); this imbalance is projected to persist over the next decade (2). Sex influences biologic drivers, etiologies, background epidemiology, markers of risk, and care quality in HF. To bolster enrollment of women in clinical trials, the U.S. Food and Drug Administration (FDA) has published a series of targeted guidance documents and regulations since the early 1990s. The FDA now requires all sponsors to include efficacy and safety data in women in applications for regulatory approval of drugs and devices, and to disclose any meaningful sex-based differences in product labeling (Online Ref. 1). The National Institutes of Health (NIH) have similarly supported adequate enrollment and reporting of sex-based subgroup information in all NIH-funded phase 3 clinical trials (Online Ref. 2).
Heart Failure Collaboratory: Improving Representation in Contemporary Trials
Since the introduction of these policies, the representation of women in contemporary clinical trials of HF has slowly improved over time (3). However, little is known about the completeness of reported sex subgroup information or whether sex influences treatment effects of investigational therapies. As such, we conducted a systematic review focused on sex subgroups in published clinical trials of HF from 2001 to 2016. The work was embedded within a larger multi-stakeholder effort, the Heart Failure Collaboratory, which includes patients, clinical trialists, industry sponsors, payers, and representatives from the U.S. FDA, NIH, and Centers for Medicare and Medicaid Services.
Systematic Query of Sex-Specific Reporting
We identified published randomized clinical trials of therapeutic interventions in HF from 2001 to 2016 using a systematic search via PubMed/MEDLINE (search terms: publication year, “heart failure,” “trial,*” and “randomized”) and ClincialTrials.gov (search limits: adult, interventional, phases II to IV, “heart failure”). We only included primary trial publications of phase 2 to 4 trials of adult populations. We set a sample size threshold (n = >400) for the total enrolled population to identify trials more likely to inform clinical practice. All procedures and reporting were by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Two independent reviewers screened all published reports for relevance and eligibility.
Key extracted data included HF categories by ejection fraction, acute HF versus chronic HF, trial phase, intervention, primary endpoint, funding source, and region of enrollment. Funding source was based on ClinicalTrials.gov entry and categorized as: 1) industry; 2) government; or 3) university or other nonprofit or non-federal organizations. We also separately identified studies specifically supported by the NIH. Enrollment rates were estimated based on study duration and expressed as patients per site per month.
Sex-specific subgroup information was searched in all primary publications and associated supplementary materials. The proportion of total trials that reported sex-specific analyses were evaluated across four 4-year periods based on publication date (2001 to 2004, 2005 to 2008, 2009 to 2012, and 2013 to 2016). We separately assessed temporal trends in phase 3 or 4 trials (when trial phase was known and/or reported). In studies with reported subgroup analyses by sex, trials were identified that had significant, unadjusted sex interaction analyses for the primary endpoint (p < 0.05). All computations were performed with IBM SPSS 23 (IBM Corporation, Armonk, New York).
Current State of Sex-Specific Reporting
In total, we screened 5,488 studies, and 118 published trials met inclusion criteria and were included. Overall, 81 (69%) trials reported outcome data by sex. The proportion of trials that reported sex-specific analyses increased from 57.1% in 2001 to 2004 to 71.9% in 2013 to 2016 (Table 1).
The proportion of women enrolled was 27%, regardless of whether the trial reported or did not report subgroup information (p = 0.75). Trials with reported subgroup information were on average larger (median: 1,325; interquartile range [IQR]: 809 to 2,426 participants vs. median: 512; IQR: 458 to 921 participants; p < 0.001) with a greater number of enrolling sites (median: 98; IQR: 42 to 244 sites vs. median: 50; IQR: 9 to 102 sites; p < 0.001). Trials that reported subgroup data were commonly global experiences with primary endpoints inclusive of mortality (p ≤ 0.001 for both). Among phase 3 or 4 trials, 76% reported sex-specific subgroup data. The proportion of sex subgroup reporting in phase 3 or 4 trials increased significantly from 50% in 2001 to 2004 to 82.4% in 2013 to 2016. Among NIH-sponsored studies (n = 12), 10 (83%) reported sex subgroup data.
Treatment Effects by Sex
Of the 81 trials that reported subgroup analyses, 77 (95%) reported no significant treatment differences by sex with respect to the primary endpoint. Of the 4 trials (5%) (Online Refs. 3–6) that did report significant treatment differences by sex, 3 evaluated endpoints that included all-cause mortality (Table 2). Sex-based subgroup analysis was among multiple subgroups tested and was pre-specified in 3 of the 4 trials. Only 1 of the 4 trials that hypothesized sex treatment differences had a primary endpoint that suggested benefit. When treatment differences by sex were identified, most reported more favorable therapeutic responses in women. One trial with a neutral overall trial result demonstrated a signal for harm with the investigational therapy versus control therapy in women, but not in men (Online Ref. 3).
A Compelling Need for Sex-Specific Data
This comprehensive systematic review demonstrates that one-quarter of large, phase 2 to 4 contemporary HF trials did not adequately report potential variation in treatment response by sex. Reassuringly, the fraction without subgroup data gradually decreased over time, and >80% of NIH-sponsored studies reported sex-specific analyses. A minority (5%) of trials identified significant variation in treatment responses to investigational therapies in HF between men and women; most of these trials reported more favorable therapeutic responses in women.
The ongoing collection and complete reporting of sex-specific data are important to identify safe and effective therapies in women for several reasons. First, the population of women with HF is growing in the United States and worldwide (2). Second, although there have been slow declines in overall rates of hospitalization for HF in older U.S. adults over the last decade, these favorable trends appear less apparent in certain sex- and race-specific groups (4). Third, sex-based differences may present biologically plausible reasons for differential treatment responses in HF. For instance, angioedema related to angiotensin-converting enzyme inhibitors, albeit rare, may occur more frequently in women, compared with men, due to sex-dependent variation in a genetic polymorphism that influences bradykinin (5). Finally, although other key demographic characteristics (e.g., race/ethnicity) influence guideline recommendations for specific HF therapies (e.g., isosorbide dinitrate/hydralazine), sex-specific guidance for individual therapies has not been proposed.
We identified few trials that reported significant sex treatment interactions with respect to primary efficacy endpoints. Three of the 4 trials found that therapies were more beneficial in women compared with men, whereas 1 trial suggested that women might have worse outcomes with vagal nerve stimulation compared with control subjects (Online Ref. 3). However, the investigators believed that this sex-based variation in treatment response was likely a function of differences in baseline clinical profiles between men and women in the trial. Importantly, none of the evaluated trials were specifically powered to assess treatment responses by sex.
There are several notable limitations of this study. Although we conducted a comprehensive systematic review of the literature using 2 different search strategies, the study was subject to publication bias, such that inclusion of only published data might have inflated the observed reporting of sex-specific subgroup data. It was possible we missed reported subgroup data that were not disclosed in the primary publication or supplementary materials. Due to heterogeneity in collection of data and reporting, we limited our systematic review to primary efficacy endpoints, and not to safety events. Finally, we were not able to dissect designations of “sex” (a term reflecting biology of reproductive organs and secondary sex characteristics) and “gender” (referring to a person’s self-identity), although the latter is typically collected in clinical trials.
A Path Forward
We observed encouraging trends in reporting of sex-based subgroup data in contemporary HF clinical trials, which might be related to dedicated efforts and requirements by regulatory agencies, funding bodies, and journals. In parallel with increasing representation of women in future clinical trials, reporting of treatment responses by sex should be complete and encompass efficacy and safety endpoints (Table 3). Clinical trials must work to adapt current binary reporting structures as sex identity classification becomes broader and more complex.
The authors would like to thank all the participants and staff involved with the multi-stakeholder Heart Failure Collaboratory for their work in promoting representation in contemporary HF trials.
↵∗ Drs. Vaduganathan and Samman Tahhan contributed equally as co-first authors of this manuscript.
Dr. Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (National Institutes of Health [NIH] National Center for Advancing Translational Sciences Award UL [1TR002541]). Dr. Samman Tahhan is supported by the Abraham J. & Phyllis Katz Foundation (Atlanta, Georgia) and NIH National Institute on Aging grant (AG051633). Dr. Greene is supported by the NIH National Heart Lung and Blood Institute T32 post-doctoral training grant (T32HL069749-14) and a Heart Failure Society of America/ Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis. This paper reflects the views of the authors and should not be construed to represent the FDA’s views or policies. Dr. Vaduganathan serves on advisory boards for AstraZeneca, Bayer AG, and Baxter Healthcare. Dr. Greene has received research support from Novartis and Amgen. Dr. Fonarow has been a consultant for Novartis, Abbott, Amgen, Bayer, Janssen, and Medtronic. Dr. Vardeny has received research support from AstraZeneca and Novartis; and consultant support from Novartis and Amgen. Dr. Lindenfeld has received grant research support from Novartis; and consultant support from St. Jude, Abbott, Relypsa, RESMED, Cardiokinetix, and CVRx. Drs. Fiuzat and O’Connor have received grant support from the NIH and Roche Diagnostics. Dr. Butler has received research support from the NIH and European Union; and has been a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CVRx, Janssen, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, Relypsa, Vifor Pharma, and ZS Pharma. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- Food and Drug Administration
- heart failure
- interquartile range
- National Institutes of Health
- Received December 17, 2018.
- Accepted December 20, 2018.
- 2019 American College of Cardiology Foundation
- Benjamin E.J.,
- Virani S.S.,
- Callaway C.W.,
- et al.
- Heidenreich P.A.,
- Albert N.M.,
- Allen L.A.,
- et al.
- Tahhan A.S.,
- Vaduganathan M.,
- Greene S.J.,
- et al.