Coronary Revascularization in Women

Abstract

Historically, mortality rates have been higher in women than in men for both PCI and CABG. Recent registries and studies have shown that women have mortality rates similar to men after correcting for age and comorbidities. The gender gap is narrowing with respect to outcomes for women with both PCI and CABG. Revascularization with PCI and CABG in women with stable angina (SA), unstable angina (UA), non ST‐elevation myocardial infarction (NSTEMI), and ST‐elevation myocardial infarction (STEMI) will all be reviewed in light of the most recent studies and registries. © 2012 Wiley Periodicals, Inc.

All American College of Cardiology Foundation/American Heart Association guidelines are published in the Journal of the American College of Cardiology and Circulation, and are available online at www.cardiosource.com and http://my.americanheart.org/professional/Statements Guidelines. The authors have no funding, financial relationships, or conflicts of interest to disclose.

Introduction

According to the American Heart Association (AHA), 150 000 women had coronary artery bypass graft surgery (CABG), and 360 000 women had percutaneous coronary intervention (PCI) in 2007. Even with these numbers, only 33% of all PCI procedures were performed in women.1 Historically, mortality rates have been higher in women than in men for both PCI and CABG.2 Some possible reasons for these results have been that women have more comorbidities such as hypertension (HTN), diabetes mellitus (DM), left ventricular dysfunction, and present at a later age compared to men. Smaller blood vessels and underutilization of practice guideline recommendations have also been cited as reasons for the disparity of outcomes in women. Women have less obstructive coronary artery disease (CAD) than men when presenting with the same diagnosis for angiography. However, recent registries and studies have shown that women have mortality rates similar to men after correcting for age and comorbidities. Revascularization with PCI and CABG in women with stable angina, unstable angina (UA), non–ST‐elevation myocardial infarction (NSTEMI), and ST‐elevation myocardial infarction (STEMI) will all be reviewed in light of the most recent studies and registries.

Stable Angina and Revascularization In Women

The American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for Chronic Stable Angina have not been updated since 2002. Since then, several large studies have compared medical therapy to interventional therapy (Table 1). In 2007, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial was published. COURAGE revealed that optimal medical therapy (OMT) without PCI in chronic stable angina, even with extensive multivessel disease and inducible ischemia, is an acceptable option. OMT with PCI did not show any benefit over OMT without PCI for primary end points of death or myocardial infarction in 2287 patients. One‐third of the patients initially stratified to OMT without PCI eventually crossed over to revascularization therapy. One of the criticisms of the study is that only 15% of the patients enrolled were women.3 Also, the OMT achieved in the trial is rarely achieved in clinical practice.

Table 1.

Summary of Studies on Coronary Revascularization in Women

Clinical Indication	Study Name	Design	Participants			Outcomes Between Men and Women	Duration of Follow‐Up (Years)
			Total	Women	%
Stable ischemic heart disease	COURAGE (1999–2004)	Randomized OMT w/ PCI, OMT w/o PCI	2287	338	14.8	Equivalent	5
Stable ischemic heart disease	BARI2D (2001–2005)	Randomized type 2 DM, Med tx alone (991), Revasc w/ CABG/PCI (953)	2368	701	29.6	Equivalent	5.3
Stable angina and unstable angina	BMC2 Registry (2002–2003)	Registry of consecutive PCI	22 725	7877	34.7	Equivalent	5
STEMI	BMC2 Registry (2003–2008)	Registry of consecutive PCI for STEMI	8771	2542	29.0	In hospital mortality higher for females (6.02% vs. 3.45%), gap narrowed over time	5
Unstable angina	British Columbia Cardiac Registry (1991–2004)	Registry, all residents w/ CABG	25 212	4983	19.8	30‐day mortality decreased in men 2.4% to 1.9%; in women 5.6 to 1.9%	14
LM disease or 3V disease	SYNTAX	Randomized to DES or CABG w/ SYNTAX score evaluation	1800	Unknown	Unknown	High SYNTAX score CABG superior for LM and 3V CAD	3
Unstable angina	“TAXUS Woman” Analysis	Meta analysis, 5 randomized trials, 2 registries	2271	665	29.3	Equivalent	5
			7492	2449	32.7
Stable CAD or acute coronary syndrome	Gender on Clinical and Angiographic Outcomes w/ DES	Meta analysis of SIRTAX, LEADERS, and RESOLUTE	4885	1164	23.8	Equivalent	2

Abbreviations: 3V, three vessel; BARI2D, Bypass Angioplasty Revascularization Investigation 2 Diabetes; BMC2, Blue Cross Blue Shield of Michigan Cardiovascular Consortium; CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; COURAGE, Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; DES, drug‐eluting stents; DM, diabetes mellitus; LEADERS, Biolimus‐Eluting Stent with Biodegradable Polymer versus Sirolimus‐Eluting Stent with Durable Polymer for Coronary Revascularisation; LM, left main; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; RESOLUTE, Comparison of the Zotarolimus‐Eluting and Everolimus‐Eluting Coronary Stents; SIRTAX, Sirolimus‐Eluting and Paclitaxel‐Eluting Stent for Coronary Revascularization; STEMI, ST‐elevation myocardial infarction; SYNTAX, Synergy Between PCI With TAXUS and Cardiac Surgery.

In the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial of over 2,300 patients with type 2 diabetes and mild or stable cardiac symptoms, over 30% of the patients were women.4 Randomization was between continued medical therapy alone and a revascularization strategy with CABG or PCI. The 5‐year mortality was 11.7% in the revascularization group and 12.2% in the medical therapy group. In the PCI strategy group, PCI was compared to medical therapy. Likewise, in the surgical strategy group, CABG was compared to medical therapy. In the PCI strategy group, all‐cause death was 10.8% in the revascularization group vs 10.2% with medical therapy. In the CABG strategy group, all‐cause death was 13.6% in the revascularization group vs 16.4% with medical therapy. There was no superiority in either the PCI group or the CABG group compared to medical therapy. This study showed that in patients with diabetes and stable angina, initial medical therapy was equally beneficial as an initial strategy compared to revascularization by PCI or CABG. However, CABG was superior in diabetic patients with severe diffuse CAD. No gender‐specific data are yet available, but this reinforces the COURAGE data for diabetic patients as well.

Another large trial since 2002 is the Women's Ischemic Syndrome Evaluation (WISE) study.5 It showed that many women without obstructive CAD have angina symptoms, poor outcomes, and poor quality of life. Women often show abnormal coronary flow reserve and elevated left ventricular diastolic pressure. Women frequently have diffuse but nonobstructive coronary atherosclerosis or microvascular disease, whereas men more commonly have obstructive epicardial coronary disease. The new guidelines will likely incorporate these large and important studies into the future recommendations for stable angina in women.

Contemporary studies show that revascularization with PCI for stable CAD in women yields outcomes similar to men. A large PCI registry, Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2), evaluated the gender differences in 22 725 consecutive procedures between 2002 and 2003.6 The registry data showed that a difference in mortality rates between men (14 848) and women (7 877) no longer exists. Most procedures were done on stable CAD patients with less than half for emergency PCI, unstable angina, or cardiac arrest. Females had more risk factors such as advanced age, DM, HTN, and congestive heart failure, but women were less often smokers and were less likely to have had a previous history of PCI or CABG. Women were less likely to be on aspirin, statins, angiotensin‐converting enzyme inhibitors, and β‐blockers. Women also had more moderate and severe chronic kidney disease. Women were more likely to have single‐vessel disease (>70%) and less likely to have 3‐vessel disease compared to men. There was no increased risk of death or major adverse cardiovascular events between female and male patients after adjusting for baseline demographics, comorbidities, clinical presentation, lesion characteristics, chronic kidney disease, and low body surface area.

UA/NSTEMI and Revascularization in Women

The 2011 ACCF/AHA Focused Update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non–ST‐Elevation Myocardial Infarction (UA/NSTEMI) was published March 2011. The current recommendations were the same for women and men with regard to pharmacologic therapy, noninvasive testing, and invasive strategies, except initial invasive strategy was not recommended for low‐risk women. More women have angina‐equivalent symptoms such as dyspnea or atypical symptoms with UA/NSTEMI than males, who tend to have more typical angina symptoms. Women tended to be older and more often have DM, HTN, and a family history but were less likely to have had a previous myocardial infarction (MI) or previous cardiac procedure. Nevertheless, women with UA/NSTEMI undergoing PCI have similar outcomes and angiographic success as men.

The European Society of Cardiology (ESC) Guidelines for ACS in Patients with NSTEMI state that both genders should be evaluated and treated in the same way. When risk factors are adjusted for, women have the same benefits as men with invasive strategies. The ESC Guidelines also recommend fondaparinux as most favorable with respect to anticoagulation.7 Future studies will need to determine if these pharmacologic treatments improve outcomes in women.

PCI and Revascularization in Women

The 2009 update to the 2005 ACC/AHA Guidelines on Percutaneous Coronary Intervention reported that contemporary studies showed improved outcomes with PCI in women. Thirty‐five percent of all PCI procedures in the United States are performed in women. The guidelines reported that compared to men, women undergoing PCI generally have more risk factors such as HTN, advanced age, abnormal lipids, and more diffuse and significant CAD.

Also in 2005, the AHA published a Scientific Statement for PCI and Adjunctive Pharmacotherapy in Women. Risks and benefits with PCI were reported as similar for men and women. Bleeding complications, a previous concern in women, were reduced with less aggressive anticoagulation regimens.8

The previously mentioned Michigan (BMC2) registry also evaluated gender differences among STEMI and primary PCI in over 8000 patients from 2003 to 2008.9 Twenty‐nine percent of the patients were female. The in‐hospital mortality rate for females was higher compared to males (6.02% vs 3.45%, P < 0.0001). However, over time the gap between the genders narrowed with respect to mortality rates. The investigators concluded the gap was largely related to advanced age and more comorbidities among the female patients. In a propensity‐matched analysis, there was no gender difference in mortality.

CABG and Revascularization in Women

Recent studies have more favorable outcomes for women with CABG than previously shown. The 2011 ACCF/AHA Guidelines for CABG surgery report that women have similar to or even better outcomes than men for long‐term outcomes. They also report that women have higher rates of periprocedural morbidity and mortality. Compared to men undergoing CABG, women still have more DM, HTN, lipid abnormalities, chronic renal insufficiency, valve disease, and lung disease.

In 2007, the British Columbia Cardiac Registry reported gender differences in 30‐day mortality after CABG in nearly 5000 women.10 The women tended to be older, have more comorbidities, and have higher ejection fractions and less extensive CAD than the 20 000 men who had CABG. The study revealed that the 30‐day mortality after CABG decreased significantly in both sexes between 1991 and 2004. However, the gains were greater in the female patients (5.6%–1.9%) compared to the male patients (2.4%–1.9%). The overall 30‐day mortality was significantly higher in women (3.6% vs 2.0%, P < 0.001) than in men despite adjusting for baseline and other factors. Like previous studies, body surface area, which may be a surrogate for coronary artery size, accounted for a large portion of the gender difference.

The 2009 Update for the ACC/AHA Guidelines of the Management of Patients with ST‐Elevation Myocardial Infarction did not address gender differences in STEMI. However, it did compare CABG with drug‐eluting stents (DES) outcomes from the Synergy between PCI with TAXUS and Cardiac Surgery (SYNTAX) trial. A recent publication on the 3‐year follow‐up of the SYNTAX trial showed that PCI with DES in patients with low SYNTAX scores for 3‐vessel disease or low to intermediate Syntax scores for left main (LM) disease have acceptable long‐term outcomes.11 However, PCI with DES still had significantly higher risk with poorer outcomes compared to CABG‐treated patients for high SYNTAX Scores in both LM and 3‐vessel‐disease patients. No gender‐specific information is available for SYNTAX as yet.

Revascularization in Women With Drug‐Eluting Stents

Currently, DES account for more than 70% of the stents used in the United States. DES usage is associated with lower rates of restenosis and target lesion revascularization (TLR). Early on, studies suggested that women and men had different diagnosis, treatment, and outcomes with DES use. Results of the “TAXUS Woman” Analysis study, which included over 3000 women, showed that women have similar benefits from PCI with DES (paclitaxel eluting) compared to men. The only exception was in the high‐risk cohort, which had a slightly higher revascularization rate.12 In Arterial Revascularization Therapies Study II (ARTS II), women treated with DES (sirolimus eluting) had significantly better outcomes than women treated with CABG in the earlier ARTS I trial.13

A meta‐analysis of 3 large randomized trials using DES for revascularization evaluated gender differences. Investigators pooled the data from these studies to evaluate mortality and MI in women at 2 years of follow‐up. The 3 studies were Sirolimus‐Eluting and Paclitaxel‐Eluting Stent for Coronary Revascularization (SIRTAX;N = 1012), Biolimus‐Eluting Stent with Biodegradable Polymer versus Sirolimus‐Eluting Stent with Durable Polymer for Coronary Revascularisation (LEADERS;N = 1707), and Comparison of the Zotarolimus‐Eluting and Everolimus‐Eluting Coronary Stents (RESOLUTE; N = 2292). Compared to men, women more frequently had DM, HTN, and obesity and tended to be older. However, women were less likely to use tobacco, or have previous MI or surgical revascularization. Also, women had lower SYNTAX scores and smaller reference diameter for target vessels. In terms of death and MI rates, women had similar outcomes after adjustment for baseline differences. Definite or probable stent thrombosis and in‐stent late loss did not differ between men and women. Finally, both women and men had similar risk with respect to TLR and target vessel revascularization.14

Conclusion

The gender gap is narrowing with respect to outcomes for women with both PCI and CABG. Women with stable angina, NSTEMI, and STEMI have improved results with revascularization compared to the results from historical studies. Women should be treated the same as their male counterparts, except for low‐risk UA/NSTEMI women. Despite the evidence that women tend to be older and have more comorbidities than men, women tend to have similar mortality rates and benefits for these procedures. Appropriateness criteria for CABG should not be affected by gender. With DES, women may even start to have some advantages in the low‐ and moderate‐risk groups. Unfortunately, the data are limited by the fact that most of these large randomized trials have low numbers of women enrolled, frequently 30% or less. Also, not all studies include analysis for gender difference. The accuracy of the data in women needs to be confirmed and requires enrolling adequate numbers of women in future studies and reporting outcomes separately by gender. Only then can we be certain that the gender gap with regard to revascularization has been eliminated.