Adequate enrollment of women in cardiovascular drug trials and the need for sex-specific assessment and reporting

Cardiovascular disease (CVD) is the leading cause of death for women in the United States and globally. There is an abundance of evidence-based trials evaluating the efficacy of drug therapies to reduce morbidity and mortality in CVD. Additionally, there are well-established influences of sex, through a variety of mechanisms, on pharmacologic treatments in CVD. Despite this, the majority of drug trials are not powered to evaluate sex-specific outcomes, and much of the data that exists is gathered post hoc and through meta-analysis. The FDA established a committee in 1993 to increase the enrollment of women in clinical trials to improve this situation. Several authors, reviewing committees, and professional societies have highlighted the importance of sex-specific analysis and reporting. Despite these statements, there has not been a major improvement in representation or reporting. There are ongoing efforts to assess trial design, female representation on steering committees, and clinical trial processes to improve the representation of women. This review will describe the pharmacologic basis for the need for sex-specific assessment of cardiovascular drug therapies. It will also review the sex-specific reporting of landmark drug trials in hypertension, coronary artery disease (CAD), hyperlipidemia, and heart failure (HF). In reporting enrollment of women, several therapeutic areas like antihypertensives and newer anticoagulation trials fare better than therapeutics for HF and acute coronary syndromes. Further, drug trials and cardiometabolic or lifestyle intervention trials had a higher percentage of female participants than the device or procedural trials.


Introduction
Cardiovascular Disease (CVD) is the leading cause of death in men and women worldwide.As pharmacologic options for treating CVD and risk factors expands rapidly, there is a growing recognition of the underrepresentation of women in clinical trials.Concurrently, there is increasing evidence of sex-based differences in biology, pharmacology, and pharmacogenomics, which would impact prescribing and dosing of these medications for women.Therefore, it is imperative that sufficient numbers of women are included in all the phases of clinical trials.
Several mechanisms influence sex differences in pharmacokinetics and pharmacodynamics in drug distribution and metabolism.Differences in drug distribution are affected by higher average percent body fat in women, the influence of sex hormones on binding proteins, lower glomerular filtration rates, and differences in blood flow and plasma volumes [1][2][3].Pharmacogenetic factors also impact response to drug therapy [3].Phase I and II enzymes have shown sex differences that could be affected by germline variants.These sex differences could lead to women exhibiting higher CYP2B6, CYP2D6, and CYP3A4 activity, whereas men exhibit higher CYP1A activity [4].Differences in Abbreviations: ARB, Angiotensin receptor blocker; ARNI, Angiotensin receptor neprilysin inhibitors; BB, Beta blockers; CAD, Coronary Artery Disease; CVD, Cardiovascular Disease; DAPT, Dual antiplatelet therapy; EPA, Eicosapentaenoic acid; HCTZ, Hydrochlorothiazide; HF, Heart failure; HFpEF, Heart failure with preserved ejection fraction; HFrEF, Heart failure with reduced ejection fraction; HR, Hazard ratio; INR, International Normalized Ratio; MI, Myocardial infarction; PCI, Percutaneous coronary intervention; PPR, participation prevalence ratio; PPAR, Peroxisome proliferator-activated receptor; RAAS, Renin-angiotensin-aldosterone system; SGLT2, Sodium-glucose-linked transporter 2 inhibitors.metabolism include sex differences in CYP450 enzymes and p-glycoprotein, which can affect the clearance of medications [1,5].Such differences can lead to higher or lower drug concentrations in women, affecting efficacy and adverse effects.For example, adverse effects of certain cardiovascular drugs have been reported more likely in women than men [1].Women have a higher risk of drug-induced torsade de pointes (at least partially related to a longer QT interval among women), cough with ACE inhibitors, hemorrhagic complications with anticoagulants, electrolyte abnormalities with diuretics, and myopathy with statins [6].Fig. 1 describes the parameters that influence drug distribution and metabolism that may be influenced by sex.
In 1993, the FDA established a committee to increase enrollment of women in clinical trials, and recently it established a website reporting "snapshots" highlighting differences among demographic groups and sex [7].This initiative aggregated data from 292,766 clinical trial participants between 2015 and 2019 of FDA-approved medications.Across all FDA studies, women comprised 49 % of participants.However, women are only approximately one-third of trial participants in cardiovascular trials.
The participation prevalence ratio (PPR) is a metric recently described that accounts for the sex-specific prevalence of the condition being evaluated (with 0.8-1.2considered adequate representation) [8].The participation of women in CVD trials by PPR is very low: congestive heart failure is 0.5, acute coronary syndrome (CAD) 0.6, atrial fibrillation 0.8, and hypertension 0.9 [8].One study compared sex-specific reporting of efficacy and safety outcomes for cardiovascular drug interventions presented at the major cardiology meetings (European Society of Cardiology, American Heart Association, American College of Cardiology) before and after the publication of the statements from these international cardiology societies emphasizing its importance [9].There were 29 trials in 2010 and 34 in 2017.There were 32.8 % female participants in the 2010 studies, which only increased to 33.4 % in 2017.Particularly disheartening was that sex-specific reporting was 34.5 % in 2010 and declined to 23.5 % in 2017, with sex-specific safety outcomes reporting declining from 11.1 % to 8.6 %.
Sex-specific results are often provided in the form of subgroup analyses.Conclusions drawn from subgroup analysis are limited, and there is evidence that subgroup analysis is often poorly conducted and reported [10][11][12].Some trials included a p-value for interaction when conducting sub-group analysis, which is important to understand a subgroup effect [13,14].However, many do not.Therefore, the inclusion of stratification by sex in a subgroup has limited utility in commenting on differences between the effects of drugs.There must be higher numbers of women involved in trials to improve these analyses.
This review evaluates female participation and sex-specific results in landmark drug trials in hypertension, lipid-lowering, anticoagulation/ antiplatelets, and heart failure.A landmark trial was defined as an influential paper that has significantly impacted the knowledge and/or clinical practice as determined by the authors' opinions and consensus.A trial search was conducted via the MEDLINE database and Google Scholar using search terms "landmark trials" and "cardiology," "heart failure," "hypertension," and "cardiovascular health."A comparison of these landmark clinical trials with the percent of women included and sex-stratified results, if provided, is explored (Fig. 2).

Blood pressure-lowering therapy
Hypertension is a key contributor to the global CVD burden and can result in a wide variety of complications.Traditionally thought of as an issue more prevalent in post-menopausal women, data from the ARIC study indicates that it may be increasing in the younger female population [15].Further, as women are delaying childbearing, hypertensive disorders of pregnancy are increasing in frequency [16].Even though antihypertensive agents are beginning to be utilized more in pregnancy, there is still a paucity of clinical trial data in pregnant women, with most drugs having limited or conflicting data with recommendations to be used with caution (formerly FDA class C or B) [17,18].
Data suggests that the female sex is likely a risk factor for hyponatremia and hypokalemia, leading to higher rates of hospitalizations in the prescription of diuretics like thiazides [19].Additionally, Fig. 1.Pharmacokinetics/dynamics in women compared to men.

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pharmacogenomic factors can influence hydrochlorothiazide (HCTZ) response via a sex-specific interaction between insertion/deletion polymorphism in the ACE gene.Better BP response was noted in females with more insertion alleles than males with deletion alleles were associated with better BP response (n = 206 individuals included in the study) [20].
Sex-related differences in renin-angiotensin-aldosterone system (RAAS) activity are present secondary to hormonal regulation.Estrogens inhibit sympathetic nerve discharge, which leads to renin production.Men tend to have higher RAAS activity when compared to premenopausal women [3].Higher peak concentrations were observed in women with commonly used angiotensin receptor blockers (ARBs).However, the differences were not significant when adjusted for weight except for peak serum concentration for telmisartan.This difference was attributed to a slower clearance.Further, there was no difference in blood pressure [21].
Landmark clinical trials in hypertension have included a range of female participants from 30 % to 67 % (Table 1).Interestingly, even early trials had a high percentage of women included.The SHEP trial in 1991 evaluated the impact of antihypertensive treatment with chlorthalidone ± atenolol on stroke risk and included 57 % women participants [22].The Syst-Eur trial was a randomized controlled trial in 1997 and evaluated blood pressure treatment with nitrendipine, enalapril, and hydrochlorothiazide.This trial included an impressive 66.8 % women, yet sex-specific outcomes were not reported.
Despite relatively higher participation of women in antihypertensive trials, there are limited sex-specific results as most studies did not provide sex-stratified findings.A sub-analysis of the ALLHAT trial (which compared lisinopril vs. amlodipine vs. chlorthalidone) found that both sexes decreased blood pressure in all treatment groups.However, the decreases in systolic BP were slightly less in women compared to men.The percentage of participants with controlled BP (<140/90) was lower in women than in men by 1-6 %, varying by treatment group.However, there was no difference in cardiovascular outcomes [23].The SPRINT trial (36 % women) found that intensive blood pressure control was associated with lower rates of major adverse cardiovascular events.Subgroup analysis found no heterogeneity of effect between men and women.Compared to the standard treatment group, the primary composite outcome in the intensive group was reduced by 16 % (HR 0.84 CI 0.61-1.13) in women and by 27 % in men (HR 0.73 CI 0.59-0.89)with a p-value for interaction 0.45 [24].
In summary, there is evidence of sex-specific differences in the reninangiotensin-aldosterone axis and response to medications secondary to Fig. 2. Scatterplot of the percentage of women in clinical trials by year Scatter plot of percent of women included in clinical trials versus year by drug category.When there was more than one trial in a given year, a weighted average was used.Overall, there was a minimal trend to increased participation of women.Most trials included <50 % of women.Seven out of 10 (70 %) blood pressure, 3 out of 22 (13.6 %) lipid, 13 out of 39 (33.3 %) antiplatelet/anticoagulation, and 14 out of 30 (46.7) heart failure trials did not include sexstratified results.
both pharmacogenetics and hormones.Landmark clinical trials in hypertension have an overall higher percentage of women, even in early trials.However, there are limited sex-specific results.

Lipid-lowering therapy
Lipid-lowering therapy is a mainstay in the prevention and treatment of cardiovascular disease in both men and women.Drugs in this category include statins, fibrates, niacin, EPA/omega 3, ezetimibe, and PCSK9 inhibitors.Historically, the earliest lipid-lowering trials in the pre-statin era (before the 1990s) included men only, such as Coronary Drug Project [26], LRC-CPPT [27], and Helsinki Heart Study [28].Female participation in lipid-lowering trials may have multiple contributing factors.As women develop cardiovascular disease later in life than men, trials that exclude older adults tend to recruit fewer female participants.This difference could be a critical factor in the lower enrollment of women in secondary prevention lipid therapy trials.For example, the PROSPER trial, which evaluated the benefits of pravastatin treatment specifically in an elderly population aged ≥70 years, successfully enrolled 52 % women [29].Another obstacle could be higher statin intolerance, resulting in higher discontinuation of statin therapy by women than men [30].Data also suggest a higher incidence of myopathy in women [31,32].
Pharmacogenetics also plays a role in lipid metabolism and response to treatment.Peroxisome proliferator-activated receptor alpha (PPARalpha), the target of fibrates, regulates the expression of several genes in lipid metabolism.One study found that fenofibrate elevated the transcriptional activation of PPAR-alpha target genes in males greater than in females [33].Other studies tested polymorphisms in the gene that encodes an estrogen receptor (ESR1) in patients treated with statins and observed sex-specific association with total cholesterol, HDL, and triglyceride levels [34,35].
Table 2 demonstrates a list of select landmark clinical trials from 1987 to 2018.Among these trials, the average participation of women was 27.3 %.As previously mentioned, several trials were men only, while some more recent trials had >50 % participation.For example, the JELIS trial, conducted in Japan, demonstrated a considerable reduction of CV events with eicosapentaenoic acid (EPA) treatment.This trial excluded premenopausal women and women older than 75 years; however, it still enrolled 68.6 % women despite those restrictions.
Some of the clinical trials demonstrated sex differences in their results.IMPROVE-IT (2017, 24 % women) showed that the addition of ezetimibe to simvastatin had a greater risk reduction in women (12 %) than men (5 %) for the primary composite endpoint [38].Sex-specific data is variable among non-LDL-focused drug therapies, including niacin, fibric acid derivatives, and omega 3-fatty acids.For example, clinical trials on niacin included only a very small proportion of women, even in more recent trials like HPS2-THRIVE (17 % women) in 2014 and AIM-HIGH (<15 % women) in 2011 [39,40].Pre-specified analysis of HPS2-THRIVE based on sex showed a trend towards worse CV outcomes in women treated with niacin (p = 0.07).
The limited number of women or lack of reporting in primary prevention trials significantly limits sex-specific analysis.Therefore most sex-specific data on outcomes is derived from meta-analyses.Two primary prevention meta-analyses from 2004 and 2010 did not show significant CVD event reduction in women with statins [41][42][43].On the contrary, in 2008, the landmark JUPITER trial was published (17,802 participants, 38 % women), demonstrating that rosuvastatin used for primary prevention reduced CV events in women and has a relative risk reduction similar to that in men [44].In addition, further analysis of their data demonstrated that women had a significantly greater reduction compared to men in revascularization/unstable angina [45].
Overall, there are sex-specific differences in lipid metabolism, pharmacogenetics, and adverse medication effects.These adverse effects may play a role in limiting the participation of women in clinical trials.Many trials did not include sex-stratification in the initial study but later performed stratified analyses.

Antiplatelets and anticoagulation
Antiplatelet agents, including aspirin, ticagrelor, clopidogrel, and prasugrel, have consistently demonstrated benefits in CAD.Oral anticoagulation agents include warfarin, apixaban, and rivaroxaban and play an important treatment role in atrial fibrillation.However, the limited inclusion of women in cardiovascular trials has restricted the research on sex differences on the effect of these drugs.
Sex-related differences in both pharmacokinetics and pharmacodynamics are present in antiplatelet and anticoagulant therapies.Numerous contributing factors include a decreased volume of distribution, differing body composition, and metabolic effects driven by hormonal differences that change in various life stages [46].Women tend to have higher platelet counts than men [47].These differences lend to extended bleeding times in women [46].Women taking warfarin experienced more minor bleeding complications than men and required less drug per week to maintain their International Normalized Ratio (INR) [48].
A comparison of 39 antiplatelet and anticoagulant landmark drug trials (including aspirin, clopidogrel, ticagrelor, prasugrel, warfarin, apixaban, and rivaroxaban) from 1988 to 2019 is shown in Table 3.The total number of participants was 447,496 across all trials, and the percentage of women included ranged from 0 % to 56.4 %.On average, the percentage of women included was 30.1.Only one trial, ASPREE (2018), had greater than half female participants.This trial evaluated aspirin versus placebo in patients >70 years of age without cardiovascular disease.This study provided sex-stratified results in a supplementary table and did not demonstrate a significant difference in results between men versus women.
Aspirin is a cornerstone of treatment for coronary artery disease.However, there is limited data studying its efficacy in women.The Women's Health Study consisted of 39,876 healthy women over 45 years, evaluating the use of aspirin in primary prevention of cardiovascular disease.It found a 17 % reduction in the risk of stroke but no significant effect on the risk of myocardial infarction or death from cardiovascular causes [49].One meta-analysis of six trials published in 2006 found that in women, aspirin therapy was associated with a 12 % reduction in cardiovascular events and a 17 % reduction in stroke but no significant effect on myocardial infarction (MI).
In contrast, for men, aspirin was associated with a 14 % reduction in cardiovascular events and a 32 % reduction in MI but no significant effect on stroke [50].This meta-analysis showed a similar risk of bleeding between the sexes.However, some studies report an increased risk of bleeding in women, at least in part due to excess dosing of drugs [51].In another study evaluating 23 trials, authors found that trials that recruited women predominantly failed to demonstrate a significant risk reduction in nonfatal MI.In contrast, predominantly men trials demonstrated the largest risk reduction in nonfatal MI [52].
The DAPT trial investigated the benefits of 30 months vs. 12 months of dual antiplatelet therapy (DAPT) in patients receiving a drug-eluting stent.In the supplementary materials for that article, the authors report a subgroup analysis where there was definite or probable stent thrombosis in continued antiplatelet therapy versus placebo in 12 (0.3 %) vs. 55 (1.5 %) men and 7 (0.6 %) vs. 10 (0.8 %) women.The hazard ratio and 95 % confidence interval for men was 0.12 (0.11-0.39) versus 0.73 (0.28-1.91) in women.The calculated p-value for interaction was 0.04, an important measure of subgroup effect.However, only 25.4 % of the 9961 total participants in this study were female.
Sex differences do not seem to play a vital role in the de-escalation of DAPT.The TROPICAL-ACS trial assessed the impact of sex on clinical outcomes and found that the primary endpoint (combined ischemic and bleeding events) was not different [53].A study in 2021 corroborated this, finding that while women had a higher bleeding risk than men, ischemic events were similar between sexes.The benefits of early aspirin withdrawal in patients after percutaneous coronary intervention (PCI) with continuing ticagrelor were comparable [54].
Out of 39 studies, 26 (66.7 %) published subgroup analysis, including effects stratified by sex.This information was usually available in a table in the text but only in supplementary materials in nine articles.Thirteen studies did not report sex-specific results, one of which had entirely male participants (Table 3).
In summary, there is evidence for sex differences in platelet and coagulation biology.However, clinical trials are quite limited in the inclusion of women.There is some evidence of a sex-based difference in bleeding risk but a general agreement of CV benefits in both women and men.However, most studies did not report sex stratification data.

Heart failure
The cornerstone for pharmacological treatment to reduce morbidity and mortality in patients with heart failure (HF) with a reduced ejection fraction (HFrEF) entails several key classes of medications, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers (BB), and mineralocorticoid receptor antagonists if the ejection fraction (EF)    is ≤35 %.New therapies that have emerged include angiotensin receptor neprilysin inhibitors (ARNI) and sodium-glucose-linked transporter 2 inhibitors (SGLT2) [55].Despite a similar lifetime risk of HF [56], female participation in clinical trials remains low.One barrier may be the higher proportion of trials targeted to HFrEF.In epidemiological studies, women with heart failure with preserved ejection fraction (HFpEF) outnumber men in a 2:1 ratio [56,57].The difference in incidence between men and women in HFpEF versus HFrEF is also represented in various disease registries.For example, of the 15,905 women enrolled in the Swedish Heart Failure Registry (n total = 42,987, 37 %), 55 % had HFpEF, 39 % had HF with mid-ranged EF, and 29 % had HFrEF [58].In that registry, women comprised 55 % of all HFpEF diagnoses but only 29 % of HFrEF diagnoses.Unfortunately, a recent review noted that women's overall enrollment in HF trials has not increased over time [59].
Studies have demonstrated some sex differences in HF pharmacology.SGLT2 inhibitors are associated with higher rates of diabetic ketoacidosis and genitourinary infections in women [60,61].Mineralocorticoid receptor antagonists interact with estrogen signaling pathways and may have differential effects based on sex.One study in rats found that eplerenone attenuated LV chamber enlargement more effectively in females than in males and improved LVEF in females only.Additionally, the transcriptomic analysis revealed that in female rats, 19 % of downregulated genes and 44 % of upregulated genes after a myocardial infarction were restored to normal with eplerenone treatment versus only 4 % of genes restored in male rats [62].Other classes of HF medications (i.e., BBs, ACE inhibitors) are discussed in the above section in hypertension.
Cytochrome 2D6 is a known genetic polymorphism, and one study evaluated CYP2D6 dependent beta-blocker (BB) (metoprolol, carvedilol, nebivolol, and propranolol) vs. independent BB (sotalol, bisoprolol, and atenolol).They noted increased adverse drug events in women compared to men for the CYP2D6 dependent BB vs. no difference in those that are independent [3,63].
Table 4 demonstrates thirty landmark HF trials from 1986 to 2020 with varying degrees of women enrolled.The total number of participants was 118,282, and the average percent participation of women was 24.1 %.The modern era of HF trials began with the Captopril Multicenter Study, showing that endpoints such as exercise capacity and symptoms can be improved [64].There were five female participants in this pivotal trial (n = 92).Later trials in the early 2000s had somewhat improved participation.For example, ValHeFT (evaluating the efficacy of valsartan) had 20.1 % female participation in 2001 and COMET (evaluating carvedilol versus metoprolol) had 20.5 % in 2003 [65].However, the percentage of women included in trials seems to have relatively plateaued.The groundbreaking PARADIGM-HF trial in 2014 established that an ARNI was superior to enalapril in reducing the risks of death and hospitalization from heart failure [66].Despite being a more recent clinical trial, there were only 21.7 % women.
In a subgroup analysis of PARAGON-HF, women had a greater reduction in HF hospitalization [67].In this study, for the primary outcome (hospitalizations for heart failure and death from cardiovascular causes), the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95 % CI, 0.59-0.90) in women and 1.03 (95 % CI, 0.84-1.25) in men (P interaction = 0.017).The difference was attributed to a reduction in HF hospitalization.The authors of that study do not propose a definite mechanistic basis for the noticed difference.However, they suggest it could be related to a higher normal left ventricular ejection fracture in women than in men or higher age-related arterial stiffening in women.Another possibility is the relationship between natriuretic peptides and sex hormones which may lead to lower levels of peptide levels in women after menopause [68].
The TOPCAT trial (52 % women) assessed the effect of spironolactone on a composite of cardiovascular death, cardiac arrest, or HF hospitalization in patients with HFpEF.While the primary analysis did not find that treatment had a significant outcome, an exploratory post-hoc analysis suggests possible sex differences in response.This analysis found no sex differences in the placebo or response arm outcomes for the primary outcome or its components.However, spironolactone was associated with reduced all-cause mortality in women (HR 0.66, p = 01) but not in men (p-value interaction = 0.02) [69].I-PRESERVE was another trial in HFpEF (investigated the role of irbesartan) and had a majority of female participation (60.3 %) [70].
In summary, HFrEF has a greater prevalence in men and HFpEF in women.There is evidence of sex differences in medication effects, which could be hormonal or pharmacogenetic, but the underlying mechanism is unclear.Almost half (n = 14) of the trials did not provide sex-stratified results.Some studies include only a graphic of a forest plot representing hazard ratios and confidence intervals without providing specific numbers, case rates, or percentages.Overall, the representation of women in HF clinical trials is low and has not increased significantly over time.

Discussion
Cardiovascular drug trials have under-enrolled women historically compared to the prevalence of cardiovascular disorders according to sex.Participation varies by disease area, with the most underrepresented areas being HF, CAD, and acute coronary syndrome.The reasons for lack of inclusion are multifactorial.In HF, differences in prevalence in HFrEF vs. HFpEF in men and women may play a role.The underenrollment of women in CAD may be related to the varied presentation of ACS in women and a lower likelihood of angiography in women, especially when used as inclusion criteria.Additionally, women tend to have less coronary artery disease and more ischemia without obstructive coronary arteries.
Age additionally may play a role.As women develop cardiovascular disease later in life than men, fewer female participants were recruited in trials that excluded older adults.One study found that CV trials were particularly low when the average participant age was 61-65 years [71].Further, barriers like ageism may reduce the rate at which older women are referred to specialists like a cardiologist [72].
Pregnant women and women of childbearing potential are frequently excluded from clinical research.This exclusion limits the number of women eligible for any given research study, and it also limits research into the effect of medications in pregnancy.
There are several sex-specific differences in drug metabolism and efficacy, and it is imperative to ensure adequate representation of both men and women when evaluating these drugs.Recent studies have addressed why these gaps may exist and how to improve participation in the future.This change will require funding to power studies to look at sex-specific outcomes, which would significantly impact the population to enroll.Further, this will necessitate investment in an infrastructure that improves patient and provider awareness and knowledge, expanding access to trial design, and adequate representation in trial leadership.Currently, the FDA has no legal requirement for trials to have a certain percentage of patients in the subgroups.The FDA could consider including gender parity in enrollment or possibly target enrollment of women equal to the composition of the disease in the population (PPR of 1).
It is important to clarify the difference between sex and gender when writing in this space.Sex refers to the biological and anatomic categorization of males and females.Gender refers to the socially constructed norms that impose and influence the way individuals interact with the world [73].This review focuses on sex or biological differences in cardiovascular pharmacology and drug effects.However, the effect of gender, namely the constraints historically and presently faced by women in our society, underpins the disparity in representation in clinical trials.Moreover, we recognize that other gender minorities, including transgender and nonbinary people, are not only underrepresented in clinical trials but that many clinical trials are limited in their reporting and inclusion of only the gender binary [74].Moreover, there is a distinct racial disparity among the women included in clinical trials.The vast majority of female cardiology clinical trial participants were white.In the FDA Snapshots in cardiology trials, among women greater or equal to 65 years, 84 % were White, 10 % Asian, 2 % Black, 4 % other, and <1 % American Indian.Among women <65, 73 % were White, 16 % Asian, 6 % Black, 5 % other, and <1 % American Indian [7].Barriers to representation are multifactorial and include community mistrust, transportation barriers, socioeconomic factors, lack of diversity in clinical trial leadership, inadequate outreach, and racism [75].It is critically important that gender parity be paired with racial parity in representation in drug trials.

Conclusion
In the future, a collaboration between clinicians, scientists, patient advocacy, government, and industry will be required to develop an infrastructure and process to expand the participation of women in cardiovascular drug trials.

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Table 1
Blood pressure.
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Table 3
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Table 3
(continued ) Abbreviations: please see abbreviation list of drug studies.C.Carland et al.

Table 4
Heart failure.
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Ischemia ALLHAT :
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial LIFE: Losartan Intervention for Endpoint reduction in hypertension study VALUE: Valsartan Antihypertensive Long-Term Use Evaluation ACCOMPLISH: Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension CORAL: Cardiovascular Outcomes in Renal Atherosclerotic Lesions PATHWAY-2: Prevention and Treatment of Hypertension With Algorithm-based therapy SPYRAL HTN-ON MED: Global Clinical Study of Renal Denervation with the Symplicity Spyra Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension on Standard Medical Therapy WOSCOPS: West of Scotland Coronary Prevention Study AFCAPS/TextCAPS: The Air Force/Texas Coronary Atherosclerosis Prevention Study LIPID: Long-Term Intervention with Pravastatin in Ischaemic Disease HPS: Heart Protection Study PROSPER: Prospective Study of Pravastatin in the Elderly at Risk ASCOT-LLA: Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm CARDS: Collaborative AtoRvastatin Diabetes Study 4S: Scandinavian Simvastatin Survival Study PROVE IT-TIMI: Pravastatin or Atorvastatin Evaluation and Infection Therapy--Thrombolysis in Myocardial Infarction 22 TNT: Treating to New Targets FIELD: Fenofibrate Intervention and Event Lowering in Diabetes MEGA: Primary prevention of cardiovascular disease with pravastatin in Japan SPRACL: Stroke Prevention by Aggressive Reduction of Cholesterol Levels JELIS: Japan EPA lipid intervention study JUPITER: Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin ACCORD-Lipids: Action to Control Cardiovascular Risk in Diabetes -Lipids AIM-HIGH: Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides HPS2-THRIVE: Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events FOURIER: Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial ODYSSEY: Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy ISIS-2: International Study of Infarct Survival 2 AFASAK: Atrial Fibrillation, Aspirin, Antikoagulation BAATAF: Boston Area Anticoagulation Trial for Atrial Fibrillation SPAF: Stroke Prevention in Atrial Fibrillation Study SPINAF: Stroke Prevention in Nonrheumatic Atrial Fibrillation ISIS-3: International Study of Infarct Survival-3 SPAF-II: Stroke Prevention in Atrial Fibrillation Study II ADMIRAL: Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-term Follow-up CURE: Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events CADILLAC: Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications SYNERGY: Superior Yield of The New Strategy of Enoxaparin, Revascularization, And Glycoprotein IIb/IIia Inhibitors COMMIT: Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study ACUITY: Acute Catheterization and Urgent Intervention Triage Strategy Trial OASIS-6: Organization for The Assessment of Strategies for Ischemic Syndromes 6 CHARISMA: Clopidogrel for High Atherothrombotic Risk, Ischemic Stabilization, Management, And Avoidance OASIS-5: Comparison of Fondaparinux and Enoxaparin in Acute Coronary Syndromes ACTIVE: Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events TRITON-TIMI: Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel HORIZONS-AMI: Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction PLATO: Platelet Inhibition and Patient Outcomes PROTECT AF: Randomized Prospective Trial of Percutaneous Left Atrial Appendage Closure Versus Warfarin for Stroke Prevention in Atrial Fibrillation RE-LY: Randomized Evaluation of Long-Term Anticoagulation Therapy CURRENT-OASIS: Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events− Seventh Organization to Assess Strategies in Ischemic Syndromes ROCKET-AF: Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation ARISTOTAL: Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation AVERROES: Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment ATLAS-ACS-2 -TIMI 51: Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction TRILOGY-ACS: Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes WARCEF: Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction WOEST: What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing ACCOAST: A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction PRODIGY: Prolonging Dual-Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia HEAT-PPCI: How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention COMPASS: Cardiovascular Outcomes for People Using Anticoagulation Strategies ASCEND: A Study of Cardiovascular Events in Diabetes ASPREE: Aspirin in Reducing Events in the Elderly ISAR-REACT: Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment C. 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