Sex-Specific Outcomes in Cardiovascular Device Evaluations

Abstract

Background:

Females have historically been underrepresented in cardiovascular device trials. As a result, differences in outcomes for males and females are not possible to be determined in subanalyses.

Materials and Methods:

Against a backdrop of troubling trends in cardiovascular outcomes for females, we provide a narrative review on the differences in outcomes observed in females undergoing device evaluations in multiple fields of cardiovascular medicine, including coronary revascularization, structural heart disease, and heart failure. We also review predictors of cardiovascular trial nonparticipation as it may provide avenues by which female enrollment in cardiovascular device trials can be improved.

Results:

Advances have been made in structural heart therapy, where female representation in transcatheter aortic valve replacement studies was nearly 50%. For other indications, coronary revascularization and heart failure, there was clearly a disparity in female recruitment. On average, female representation was 25% in major clinical trials evaluating drug eluting stents, implantable cardioverter defibrillators, cardiac resynchronization defibrillators, and ventricular assist devices. As a result, the best treatment recommendations for females in these fields are currently guided by outcomes evaluated primarily in males.

Conclusions:

Female enrollment in device clinical trials for coronary revascularization and heart failure has lagged, leaving uncertainty in making benefit/risk assessments of device therapy. The predictors of female nonparticipation in clinical trials can inform a comprehensive strategy to facilitate and enrich the enrollment of females in cardiovascular device trials. This is critical to ensure that sex differences can be considered in treatment selection, so that patients can receive the best available care.

Introduction

Female participation in cardiovascular clinical trials has been lacking. In one recent analysis of publicly available FDA review data from 36 drug approvals between 2005 and 2015, female participation to prevalence ratios were 0.5–0.6 (heart failure), 0.6 (coronary artery disease [CAD]), and 0.6 (acute coronary syndrome [ACS]/myocardial infarction [MI]). Gender differences in efficacy or safety were only described in labeling for four drugs (11%).¹ Similar observations have been made for females in cardiovascular device investigations. One systematic review of 78 high-risk cardiovascular devices, which received FDA premarket approval between 2000 and 2007, revealed that 34 of 123 (28%) studies failed to report the sex of enrollees. When sex was reported, males represented an average 67% of study populations.²

Evidence-based medicine relies on data with adequate power for detecting differences in sex-specific outcomes, and yet, the lack of female participation in cardiovascular device investigations presents as a major obstacle. As a result, differences in sex-specific outcomes are not possible to be determined in post hoc analyses, systematic reviews, or meta-analyses, casting doubt on the reliability of the data.

The evidence for sex disparities in cardiovascular treatment warrants measures to increase female participation to ensure that females receive the best available care. In the present review, we explore sex-specific outcomes in clinical trials evaluating cardiovascular devices for coronary revascularization, structural heart disease, and heart failure. Finally, we review reasons for female underrepresentation and summarize a comprehensive strategy with well-defined steps to facilitate and enrich the enrollment of females in cardiovascular device trials. These are necessary actions to reduce the gap in gender-based evidence and to ensure a better understanding of sex-specific outcomes with the ultimate goal to improve the outcomes and standards of care for females with cardiovascular disease (CVD).

Evidence for Sex Disparities in Cardiovascular Treatment and Outcomes

Equitable care is, in part, driven by receiving standard treatments or procedures that are supported by reliable clinical evidence. However, females are unlikely to receive the same standard treatments that males receive. Younger females with ST-segment elevation myocardial infarction (STEMI) undergo fewer life-saving revascularizations and have higher in-hospital mortality compared with men.³ Females with STEMI are less likely to receive reperfusion therapy, and when they do, are more likely to have delays, and more often exceed recommended in-hospital transfer times for primary percutaneous coronary intervention (PCI),⁴ and door-to-balloon times are on average 16 minutes longer compared with males.⁵

These disparities are not unique to females in the United States and cannot be attributed to the U.S. health system alone. In Canada, females with ACS are less likely than males to receive beta-blockers, lipid-modifying agents, angiotensin-converting enzyme inhibitors (ACE-I), and may not be referred for cardiac catheterization.⁶ In Sweden, high-risk females with suspected CAD referred for coronary angiography receive aspirin less often compared with males⁷ and are less likely to receive guideline-indicated care for STEMI or non-STEMI.⁸ Females, especially those older than 65 years, delay seeking care for symptoms of acute myocardial infarction (AMI).⁹

After implementation of a four-step protocol for STEMI care, there were no significant differences between males and females for guideline-directed medical therapy, door-to-balloon times, and in-hospital adverse events.¹⁰ This demonstrates that a systems-based approach can lead to improvements in care for females with CVD. These are but a small subset of observations consistently demonstrating that females do not receive equitable care, and that, not infrequently, the care they do receive may be suboptimal or inappropriate.

Socioeconomic factors such as income have also been observed to play a consistent role in cardiovascular outcomes. Female income has long lagged behind male income.¹¹ A recent pooled analysis of a new generation of drug eluting stents (DESs) in all comers highlighted that heterogeneity conferred by gender introduces both intrinsic (biologic) and extrinsic factors (social, behavioral, cultural, and economic factors) impacting cardiovascular outcomes, and has a significant role in recruitment into clinical trials.^12,13 An annual income <$25,000 was associated with a higher composite rate of death, MI, or target vessel revascularization (TVR) compared with those with an annual income >$50,000 (9.8% vs. 4.1%), and income was an independent predictor of death and combined death/MI even after adjustment for all other significant clinical variables.¹⁴

Another study showed that the incidence for heart failure hospitalization was higher in females with household incomes <$20,000/year compared with >$50,000/year (57.3/10,000 person-years vs. 16.7/10,000 person-years; p < 0.01).¹⁵ Patients with Medicaid and patients without insurance were less likely to receive a DES in a cohort undergoing PCI.¹⁶ An analysis of a national registry revealed that patients with peripheral artery disease receiving care at low-income areas are less likely to receive appropriate secondary prevention such as statins and antiplatelet therapy.¹⁷ Before passage of the Affordable Care Act, over one in eight hospitalizations for AMI and stroke occurred in adults <64 years of age without insurance.¹⁸ Lack of health insurance and low household income in patients presenting with STEMI are independently associated with worse in-hospital mortality.¹⁹

Income disparities are also linked to the presence of cardiovascular risk factors such as systolic blood pressure, smoking status, diabetes, and total cholesterol.²⁰

Sex-Specific Results from Cardiovascular Device Studies

Coronary artery disease

CAD is the largest contributor to female CVD-related deaths²¹ and clinical outcomes for females with CAD are concerning. Females treated for CAD are older and have a higher prevalence of comorbidities than males. Following PCI, females are at increased risk for in-hospital death, vascular complications, bleeding, stroke, and major adverse cardiac and cerebrovascular events compared with males (Table 1), even after adjustment for risk factors including impaired kidney function and low body surface area.^22
–24 Despite the use of vascular closure devices and radial access, women undergoing PCI continue to experience higher bleeding and vascular complications.^25,26

Table 1.

Coronary Artery Disease: Female Sex-Related Clinical Outcomes After Percutaneous Coronary Intervention

Study	N	Females (%)	Outcomes
			Endpoints	Females (%)	Males (%)	Significance, females vs. males
			Endpoints	Females (%)	Males (%)	OR (95% CI)	p
Belgium, BWGIC, PCI Registry²³	130,985	27.4	In-hospital
			Major bleeding	0.6	0.4	1.58 (1.33–1.86)	<0.0001
			Death	2.5	1.6	1.57 (1.44–1.70)	<0.0001
			MI	0.8	0.7	1.22 (1.06–1.40)	0.001
			CVA	0.3	0.2	1.50 (1.17–1.91)	0.001
			Renal failure	0.6	0.4	1.32 (1.11–1.56)	0.001
			ST	0.4	0.5	0.84 (0.70–1.02)	0.083
			MACCE	3.1	2.0	1.55 (1.44–1.67)	<0.0001
Paris, PCI Registry (STEMI)²⁴	16,760	21.9	In-hospital
			Death	9.8	4.3	1.38 (1.16–1.63)	0.0002
			Transfusion	1.2	0.4	3.33 (2.19–5.09)	<0.0001
			Stroke	0.5	0.2	2.57 (1.40–4.72)	0.002
ACUITY Trial²²	13,819	30.0	30-Days
ACUITY Trial²²	13,819	30.0	Major bleeding	2.3%	2.4%	1.92 (1.61–2.29)	<0.0001
TAXUS Woman Analysis (RCTs)²⁸	2271	29.3	Up to 5 years	HR/year	HR/year
			Death	2.1	1.9		0.54
			MI	1.9	1.6		0.42
			ST	0.3	0.6		0.13
			TLR	2.9	2.7		0.67
Pooled Analysis, TWENTE and DUTCH PEERS Trials³¹	3202	27.2	2 Years
			Death	4.5	3.4	1.30 (0.88–1.92)	0.18
			MI	3.7	3.9	0.93 (0.62–1.40)	0.72
			TVR/TLR	8.5	8.6	0.98 (0.74–1.30)	0.90
			ST	0.5	0.8	0.59 (0.20–1.76)	0.34
			MACE	10.4	10.1	1.03 (0.80–1.33)	0.82
			Chest pain	17.2	11.1	1.66 (1.32–2.10)	<0.001
Pooled Analysis, PLATINUM Diversity, PROMUS Element Plus¹²	4182	44.5	1 Year
			MACE	8.6	7.6	1.1 (0.87–1.47)	0.35
			Death/MI	5.0	3.1	1.6 (1.11–2.39)	0.01
			MI	1.9	1.1	1.7 (0.91–3.09)	0.09

ACUITY, Acute Catheterization and Urgent Intervention Triage strategY; BWGIC, Belgian Working Group on Interventional Cardiology; CI, confidence interval; CVA, cerebrovascular accident; DUTCH PEERS, Durable Polymer-Based Stent Challenge of Promus Element versus ReSolute Integrity in an All Comers Population; HR, hazard ratio; MACCE, major adverse cardiac and cerebrovascular events; MACE, major adverse cardiovascular events; MI, myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; ST, stent thrombosis; STEMI, ST-segment elevation myocardial infarction; TLR, target lesion revascularization; TVR, target vessel revascularization; TWENTE, The Real-World Resolute Versus Xience V Drug-Eluting Stent in Twente.

The lack of sex-specific results contributes to the gap in understanding the clinical outcomes. Females enrolled in device approval trials are rarely representative of real-world patients. Whereas large-scale all-comers registries enroll >33% female patients, female representation was typically <25% among 26 randomized approval DES trials.^27,28 In addition, females have been excluded from randomized trials of AMI due to age.^29,30 This further contributes to misrepresentation of the general population at risk, and questions the generalizability of trial results to all females. Due to limited primary female data, sex-specific outcomes often rely on pooled patient level data and meta-analyses. Still, data from these studies fail to address the complexity of CVD management in females with CAD.

Despite the lack of large-scale DES trials, meaningful attempts to explore sex differences in clinical outcomes have been made. A “TAXUS Woman” analysis, including five randomized trials, showed no significant sex-based differences in death, MI, stent thrombosis, or target lesion revascularization through 5 years (Table 1).²⁸ A patient-level, pooled analysis of two next-generation DESs in all comers, at 2-year follow-up, reported for females and males similar rates for death, MI, all revascularization, and stent thrombosis and higher rates of “clinically relevant chest pain” for females, compared with males (17.2% vs. 11.1%; p < 0.001) (Table 1).³¹ The underpinnings of the higher rates of angina are not clear but suggest the possible contribution of microvascular dysfunction.³¹

Dedicated studies (mostly government funded) evaluate sex-specific factors, including hormonal status, as potential correlates to the extent of CAD and clinical outcomes in females.^32,33 However, to our knowledge, no device trial or registry of coronary stents has included hormonal history (i.e., history of pregnancy, hormone replacement therapy, gestational diabetes, polycystic ovarian syndrome, menstrual cycle history) or other sex-specific measures to better characterize and elucidate the contribution of micro- and macrovascular disease to clinical outcomes.^34,35 The clinical endpoints in standard stent trials clearly do not capture relevant data points specific to females and represent one of the greatest missed opportunities.

A substudy of FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) evaluated sex differences in PCI decision-making and addressed some of the challenges in managing females with multivessel CAD.³⁶ Fractional flow reserve (FFR) values were higher in females than in males (0.75 ± 0.18 vs. 0.71 ± 0.17; p = 0.001). Females (n = 261, 26%) were less likely than males to have functionally significant lesions (FFR ≤0.80), for lesions with a visual 50%–70% angiographic stenosis (21.1% vs. 39.5%; p < 0.001) as well as for lesions with 70%–90% stenosis (71.9% vs. 82.0%; p = 0.019), but not for lesions with 91%–99% stenosis (97.5% vs. 96.2%; p = 0.682).³⁶ The relatively higher FFR values in women emphasizes the importance of functional assessment to guide interventional therapy and suggests that microvascular dysfunction plays a key role in the pathophysiology of CAD in females.

Nevertheless, improvements in stent design (smaller stent sizes, thinner struts, biocompatible polymers in newer generation DESs and polymer-free stents) have proven to be particularly relevant in females who have smaller and more tortuous coronary arteries. A pooled patient-level analysis, including 11,557 females enrolled in 26 randomized trials for DESs, showed a significantly lower cumulative incidence of 3-year composite death or MI events with newer generation DESs when comparing with early generation DESs or bare metal stents (9.2% vs. 10.9% vs. 12.8%, p = 0.001).³⁷

It is important to note that the PLATINUM Diversity study enrolled 1501 patients to be treated with everolimus-eluting stents with the only inclusion criteria being female sex or a minority race.¹² Data from the PLATINUM Diversity were pooled with an observational study (PROMUS Element Plus Post-Approval Study) evaluating 1-year outcomes following PCI with everolimus-eluting stents in all-comers.¹³ The pooled analysis showed that females had an increased risk of the combined endpoint of death or MI (Table 1) and a trend for greater risk of nonstent-related MIs (0.8% in females vs. 0.3% in males, p = 0.05).¹² “Device failure” alone was unlikely to account for the observed differences given the similar rates of stent thrombosis and TVR. The analysis of the PLATINUM Diversity study also showed that a higher composite rate of death, MI, or TVR was more likely to be associated with a lower annual income <$25,000 compared with an annual income >$50,000 (9.8% vs. 4.1%), and income was an independent predictor of death and combined death/MI event after adjustment for all other clinical and angiographic variables.¹⁴

Structural heart disease

Female representation in transcatheter aortic valve replacement (TAVR) studies is significantly higher compared with CAD trials.^38
–40 Nearly 50% of patients undergoing TAVR are females, which is a likely result of higher life expectancy and patient preference for a less morbid, minimally invasive approach.⁴¹ Nevertheless, females undergoing TAVR experience higher periprocedural complications than males. Evidence from meta-analyses shows that female sex is associated with higher rates of major bleeding, vascular complications, blood transfusions, and stroke at 30 days (Table 2).^42,43 Known contributors for TAVR periprocedural complications include age, lower body surface area, and smaller diameter vessels.^42,44 However, long-term survival after TAVR in females is significantly better compared with males, potentially caused by lower cardiovascular mortality (Table 2).

Table 2.

Structural Heart Disease: Female Sex-Related Clinical Outcomes After Transcatheter Aortic Valve Replacement

Study	N	Females (%)	Outcomes
			Endpoints	Females (%)	Males (%)	Significance, females vs. males
			Endpoints	Females (%)	Males (%)	RR (95% CI)	p
Saad et al.⁴³	47,188	49.4	30 Days
			Vascular complications	9.3	5.4	1.62 (1.35–1.94)	<0.001
			Stroke/TIA	3.1	2.3	1.28 (1.04–1.57)	0.02
			Major bleeding	13.5	9.9	1.37 (1.27–1.48)	<0.001
			Transfusion	26.4	17.1	1.51 (1.04–2.18)	0.03
			Death	6.2	5.3	1.09 (0.96–1.24)	0.19
			≥3 Years
			Death	36.7	42.9	0.87 (0.81–0.92)	<0.001
			Cardiovascular death	11.9	14.6	0.80 (0.68–0.95)	0.009
O'Connor et al. ⁴²	11,310	48.6	30 Days			OR (95% CI)
			Vascular complications	6.3	3.4	1.89 (1.58–2.26)	<0.0001
			Stroke	4.4	3.6	1.22 (1.01–1.47)	0.03
			Major bleeding	10.5	8.5	1.28 (1.09–1.49)	0.002
			Death	6.5	6.5	0.99 (0.86–1.16)	0.93
			(median 387 days)			HR (95% CI)
			Death	26.0	32.2	0.79 (0.72–0.87)	<0.001
PARTNER Trial³⁸	699	43	2 Years	TAVR vs. SAVR	TAVR vs. SAVR	HR (95% CI)
PARTNER Trial³⁸	699	43	Death	28.2 vs. 38.2	32.3 vs. 37.7	0.67 (0.44–1.00)	0.049
CoreValve US High Risk Pivotal Trial³⁹	353	100	1 Year
			Death	12.7 vs. 21.8			0.03
			Death or major stroke	14.9 vs. 24.2			0.04

PARTNER, Placement of AoRTic TraNscathetER Valve; RR, risk ratio; SAVR, surgical aortic valve replacement; TAVR, transcatheter aortic valve replacement; TIA, transient ischemic attack.

In the PARTNER (Placement of Aortic Transcatheter Valve) trial, long-term, 2-year mortality rate was lower in high-risk females with severe aortic stenosis undergoing TAVR, compared with surgical aortic valve replacement (SAVR).³⁸ The survival benefit with TAVR compared with SAVR was observed for females, but not for males (Table 2) and was consistent with transfemoral approach (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.32–0.93; p = 0.02).³⁸ In the female cohort of the CoreValve US High Risk Pivotal Trial, TAVR demonstrated a significant benefit over SAVR for 1-year mortality and composite of mortality or major stroke (Table 2).³⁹ However, these differences in outcomes for females should be considered hypothesis generating and certainly warrant further investigations.

WIN-TAVI (Women's International Transcatheter Aortic Valve Implantation) is an all-female TAVR registry with a collection of female sex-specific baseline parameters such as history of pregnancy, pregnancy-induced complications, osteoporosis, gynecologic or breast cancer, and gynecologic surgery. In this study, reproductive history carried prognostic value for the 30-day composite safety endpoint. Pregnancy with at least one live birth was associated with a lower risk of the 30-day Valve Academic Research Consortium (VARC)-2 safety composite endpoint, even after adjusting for baseline characteristics (odds ratio 0.57; 95% CI: 0.37–0.85; p = 0.007)—a finding that requires further study as the correlation between a pregnancy from decades before TAVR and 30-day outcomes is unclear.⁴⁵

While female reproductive history is emphasized in CVD prevention guidelines,^46,47 these findings are relevant to device trials; not just for understanding the relation to outcomes in future TAVR studies but also as examples for studies across all domains of cardiovascular medicine. Routine acquisition of expanded sex-specific characteristics may provide valuable insights in narrowing the gap in outcomes between sexes.

Heart Failure

Implantable cardioverter defibrillators

Among studies of devices in heart failure, females have been grossly underrepresented. Randomized trials evaluating implantable cardioverter defibrillators (ICDs) for primary prevention of sudden cardiac death comprised only 16%–30% female patients (Table 3).^48

–51 As most of these trials enrolled patients with heart failure and reduced ejection fraction, the lower female participation might be partially explained by the higher prevalence of heart failure with preserved ejection fraction among females.⁵² Still, ICDs for primary prevention are used disproportionately, more frequently in males (32.3 per 1000, n = 65917) versus females (8.6 per 1000, n = 70504) even after consideration of the prevalence of heart failure with reduced ejection fraction (HR 3.15; 95% CI [2.86–3.47]).^53,54

Table 3.

Heart Failure: Major Implantable Cardioverter Defibrillator and Cardiac Resynchronization Defibrillator Trials

RCT	N	Females (%)	Randomization	HR for events		p Value interaction
RCT	N	Females (%)	Randomization	Male	Female	p Value interaction
ICD therapy
SCD-HeFT⁴⁸	1676	23	ICD vs. placebo	Death (median 45.5 months)		0.34
SCD-HeFT⁴⁸	1676	23	ICD vs. placebo	HR 0.73, CI 0.57–0.93, p = 0.013	HR 0.96, CI 0.58–1.61, p = 0.87	0.34
DEFINITE⁴⁹	458	29	ICD vs. medical therapy	Death (mean 29.0 ± 14.4 months)		0.11
DEFINITE⁴⁹	458	29	ICD vs. medical therapy	HR 0.49, CI 0.27–0.90, p = 0.018	HR 1.14, CI 0.50–2.64, p = 0.754	0.11
MADIT II⁵¹	1232	16	ICD vs. medical therapy	Death (average 20 months)		0.72
MADIT II⁵¹	1232	16	ICD vs. medical therapy	HR 0.66, CI 0.48–0.91, p = 0.011	HR 0.57, CI 0.28–1.18, p = 0.132	0.72
DANISH⁵⁰	556	27	ICD vs. medical therapy	Death (median 67.6 months)		0.66
DANISH⁵⁰	556	27	ICD vs. medical therapy	HR 0.85, CI 0.64 − 1.12, p = 0.24	HR 1.03, CI 0.57 − 1.87, p = 0.92	0.66
CRT-D therapy
MADIT-CRT⁶¹	1820	25	CRT-D vs. ICD	Death or heart failure (average 2.4 years)		<0.01
				HR 0.72, CI 0.57–0.92, p < 0.01	HR 0.31, CI 0.19–0.50, p < 0.01	<0.01
				Death		<0.03
				HR 1.05, CI 0.70–1.57, p = 0.83	HR 0.28, CI 0.10–0.79, p = 0.02	<0.03
				Heart failure		<0.01
				HR 0.65, CI 0.50–0.84, p = 0.001	HR 0.30, CI 0.18–0.50, p < 0.001	<0.01
RAFT⁶³	1798	17	CRT-D vs. ICD	Death or heart failure hospitalization (mean 44 ± 18 months)		0.09
RAFT⁶³	1798	17	CRT-D vs. ICD	HR 0.82, CI 0.7–0.95, p < 0.01	HR 0.52, CI 0.35–0.85, p < 0.01	0.09
REVERSE⁶⁴	610	21	CRT-D vs. CRT-P	Mortality (>5 years)
					HR 0.07, p < 0.01

CRT-D, Cardiac resynchronization therapy with defibrillator; CRT-P, CRT pacemaker; DANISH, Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality; DEFINITE, Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; ICDs, implantable cardioverter defibrillators; MADIT II, Multicenter Automatic Defibrillator Implantation Trial II; MADIT-CRT, Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy; RAFT, Resynchronization-Defibrillation for Ambulatory Heart Failure Trial; REVERSE, REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction; SCD-HeFT, Sudden Cardiac Death in Heart Failure Trial.

To some extent, sex-based differences in the use of ICDs may be attributable to differences in age at presentation. Female patients tend to be older than men when diagnosed with ischemic heart disease or cardiac arrest and physicians may be less likely to recommended ICD therapy in the elderly and octogenarians with lower expectation of survival.⁵³

The increase in the use of ICD therapy in more recent years suggests that while racial disparities are less pronounced, sex-disparities still persist.⁵⁵ These studies are, however, underpowered to detect differences in the smaller subsets of females enrolled in these trials.⁵⁶ In the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), the ICD therapy versus placebo provided survival benefit for males while demonstrating no significant survival benefit for females (Table 3).⁴⁸

Similarly, the DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation) and the MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) trials reported a survival benefit for males treated with an ICD versus standard medical therapy, but not for females (Table 3).^49,51,57 However, none of these studies was powered to detect sex differences and the interaction between gender, ICD therapy, and mortality was not significant (Table 3). With advances in medical therapy, the more recent DANISH (Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality) trial found no survival benefit for either males or females and no significant treatment-by-subgroup interaction for females versus males (Table 3).⁵⁰

In a propensity-matched analysis, including patient data from the Get With The Guidelines for Heart Failure registry, and Medicare and Medicaid Services, a primary prevention ICD was associated with a significant survival advantage among both females and males.⁵⁸ The cumulative mortality risk at a median 3-year follow-up was significantly lower in females with an ICD (n = 430) compared with those without (n = 430; HR: 0.78; 95% CI, 0.66–0.92; p = 0.0003). The survival benefit observed in females was comparable with that in male-matched cohorts with an ICD (n = 859) and without (n = 859; HR: 0.76; 95% CI, 0.67–0.87; p < 0.001).⁵⁸ A test for interaction demonstrated that improved survival associated with an ICD implantation did not depend on sex (p = 0.79).

A multicenter, prospective study of 6021 patients (21.4% females) referred for ICD implantation reported that females were more likely to experience major complications by 1 year (HR: 1.91, 95% CI:1.48–2.47; p < 0.001) and less likely to receive an appropriate ICD shock (HR: 0.69, 95% CI:0.51–0.93; p = 0.015).⁵⁹

Cardiac resynchronization therapy

Females were also underrepresented in cardiac resynchronization therapy (CRT) for heart failure, comprising only 20% of the total population reviewed by the FDA.⁶⁰ In the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with CRT) trial females benefited significantly more from CRT with defibrillator (CRT-D) compared with males with respect to a composite of death or heart failure, heart failure or death events (Table 3).⁶¹ The sex-by-treatment interactions for mortality reduction were significant in females versus males as well. These favorable outcomes for females compared with men were attributed to echocardiographic evidence of reverse remodeling.⁶²

Similarly, the Resynchronization-Defibrillation for Ambulatory Heart Failure (RAFT) trial demonstrated survival benefit for females compared with males for composite of death or heart failure endpoint when adding CRT to an ICD (Table 3).⁶³ Moreover, the resynchronization reverses remodeling in systolic left ventricular (REVERSE) dysfunction trial determined improved long-term survival for females on multivariable analysis (Table 3).⁶⁴

An FDA patient-level, pooled meta-analysis, including data from MADIT-CRT, RAFT, and REVERSE trials counting 878 (22%) females, showed that females with mild heart failure and left bundle branch block (LBBB) benefited more from CRT-D than ICD at a shorter QRS duration than men.⁶⁰ With a QRS duration of 130–149 mseconds, female versus male sex was associated with a composite endpoint (heart failure or death) benefit from CRT-D when compared with ICD (HR: 0.24, 95% CI 0.11–0.53; p < 0.001 versus HR: 0.85, 95% CI 0.60–1.21; p = 0.38, p _interaction = 0.003).⁶⁰

Yet, professional society guidelines limit recommendations for CRT-D class I indications for patients with LBBB and a QRS duration ≥150 mseconds, based on evidence derived from predominantly male data.⁶⁵ While there are class IIA indications for patients with a shorter QRS interval, professional society guidelines do not, and yet should, emphasize sex-specific differences, as female patients were 3 times less likely to receive life-saving CRT-D therapy than males in one large monitoring database from 2008 to 2011.⁶⁶

Moving forward, strong efforts must be made to include females in trials investigating new devices, emphasizing regulatory labeling considerations, with a deliberate emphasis on sex-based evidence and recommendations in professional society guidelines.

Ventricular assist devices

In females, deaths attributable to CAD account for almost 50% of CVD deaths, while deaths due to heart failure carry an additional 35% to the total CVD mortality burden.⁶⁷ Ventricular assist devices (VADs) have gained importance in the treatment of end-stage heart failure mainly due to a growing organ shortage. Yet, females remain underrepresented in trials for VADs as well.⁶⁸ This is despite the fact that females often present with more advanced, decompensated heart failure compared with males.⁶⁹

The largest European registry of patients with mechanical circulatory support (EUROMACS), including 151 females (16%), reported that females receiving VADs experienced more complications than males, including major bleeding, arrhythmias, and right ventricular (RV) failure with need for additional RV support. Cox regression analyses showed that in females, pump thrombosis was strongly associated with mortality compared with men (HR: 10.01; 95% CI, 4.44–22.55; p < 0.001 vs. HR: 3.27; 95% CI, 2.07–5.16; p < 0.001, p _interaction = 0.028).⁷⁰ In addition, female patients are at a higher risk for stroke after VAD implantation than men (multivariable HR for female sex 3.1; 95% CI: 1.4–6.9; p = 0.007).⁷¹ A propensity score-matching analysis for VAD as a bridge to transplantation determined that half (50%) of female recipients required short-term postoperative RV support compared with 16.7% in the male group (p = 0.014).⁷² These differences remain poorly understood.

Reasons for Underrepresentation in Clinical Trials: Patient- and Trial-Related Factors

Patient- and trial-related factors for enrollment in cardiovascular device trials must be distinguished from each other in a comprehensive strategy to improve female participation.

Table 4 summarizes predictors of cardiovascular trial nonparticipation and methods that can be used to address these barriers. Multiple patient- and trial-specific factors were identified with trial nonparticipation in an examination of patient screening logs for cardiovascular randomized-controlled trials at a high-volume US academic health system.⁷³ Age ≥65 years and female sex were patient-specific predictors of trial nonparticipation, while trial-specific predictors included lack of compensation, longer trial duration, and intensive testing. Transportation challenges and adverse health effects have also been cited by women as reasons to decline participation in cardiovascular trials.⁷⁴ A better and more thorough understanding of the reasons females choose not to participate in cardiovascular trials can be utilized to improve the enrollment.⁷⁵

Table 4.

Predictors of Cardiovascular Trial Nonparticipation and Potential Methods to Address Nonparticipation

Predictors of cardiovascular trial nonparticipation	Methods to increase enrollment
Patient-specific
Age ≥65	—
Female sex	Diversify clinical teams
Transportation issues	Provide transportation tokens and ancillary services
Adverse health effects	Demystify the clinical trial process and emphasize standard of care
Trial-specific
Lack of compensation	Provide ancillary services to offset cost of participation
Longer trial duration	Allow primary care providers to perform follow-up visits
Intensive testing	Allow primary care providers to perform follow-up visits

Conclusions

Given the poor evidence for female-specific outcomes in cardiovascular device evaluations, investments must be made to ensure that a robust strategy for sex-specific data collection is available for females. Although advances have been made in device evaluations for structural heart disease, female enrollment in trials for coronary revascularization and heart failure lagged behind leaving uncertainty in making benefit/risk assessments of device therapy. It is no longer acceptable that best treatment recommendations for females be guided by outcomes primarily evaluated in males. The predictors of female clinical trial nonparticipation can be leveraged into a comprehensive strategy with well-defined steps to facilitate and enrich the enrollment in device evaluations and end a perpetuating cycle of poor outcomes. These necessary actions are needed to ensure that sex differences are considered in treatment selection for females to receive the best available care.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

M.I.G. was funded by the Yale University School of Medicine Medical Research Fellowship.

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