Sex and Ethnicity Issues in Interventional Cardiology

Characteristics and Outcomes of Women Undergoing Percutaneous Coronary Intervention

More than 1.3 million percutaneous coronary interventions (PCIs) are performed annually in the United States, with an estimated 35% performed in women. Compared with men, women undergoing PCI are 5 to 10 years older and have a higher prevalence of hypertension, hyperlipidemia, diabetes, and other comorbidities such as smoking. They are less likely to have a history of myocardial infarction (MI), PCI, or coronary artery bypass graft (CABG) surgery. Women are more likely to present with non–ST-elevation acute coronary syndromes (NSTE-ACS), whereas men are more likely to present with an ST-elevation MI (STEMI). Compared with men, women have similar lesion types but less multivessel disease and substantially smaller vessels. Despite a lower prevalence of left ventricular dysfunction at baseline, women tend to have a higher incidence of congestive heart failure (CHF) and cardiogenic shock, and they have more functional impairment after revascularization than do men.

Early reports of patients undergoing balloon angioplasty showed lower procedural success rates in women. In addition, early registry data found that women had higher in-hospital mortality after PCI even after adjusting for baseline comorbidities. However, more recent studies report similar procedural success rates in both groups, with an increase in the number of women undergoing PCI over the past several decades. Overall these studies demonstrate that both in-hospital and long-term mortality rates after PCI are similar between men and women despite women being older and having more complex lesion types ( Tables 9.1 and 9.2 ). This is likely due to heightened awareness of the effects of CVD on women, as well as advances within the field (i.e., newer-generation stents and balloons, smaller sheath sizes and catheters, and advances in adjunctive pharmacotherapies). Controversy has surrounded the previously documented, less frequent use of diagnostic catheterization and delays in PCI in women compared with men. These issues will be addressed further in the section on acute coronary syndromes (ACSs) later in the chapter.

Sex and Percutaneous Coronary Devices and Adjuvant Therapies

No sex-based comparisons were made in the earlier randomized clinical trials comparing bare-metal stents (BMSs) with balloon angioplasty. Restenosis and revascularization rates were not well defined for women after bare-metal stenting because of the small sample of women in prospective trials with systematic angiographic follow-up. Even though women tend to have smaller vessel size, shorter lesions, and a higher prevalence of diabetes, some intriguing initial studies reported that women had similar or lower target-vessel revascularization (TVR) rates compared with their male counterparts after PCI. However, systematic angiographic and clinical follow-up has not validated these findings. In the drug-eluting stent (DES) era, both sirolimus and paclitaxel stents have shown favorable outcomes in women. The Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions (SIRIUS) trial and the TAXUS IV trial demonstrated the superiority of DESs with reduction in restenosis, TVR, and major adverse cardiac events (MACEs) at 1-year follow-up in women and men. TAXUS IV randomized patients with severe coronary artery stenosis to DES (paclitaxel) versus BMS. Women accounted for 27.9% of the study population. Restenosis rates were similar in women and men treated with the TAXUS stent (7.6% vs. 8.6%, P = .80), as were measurements of late luminal loss (0.23 mm vs. 0.22 mm, P = .90). Compared with BMSs, women treated with the TAXUS stent had a significant reduction in 9-month restenosis (29.2% vs. 8.6%, P < .001) and 1-year target-lesion revascularization (TLR) rates (14.9% vs. 7.6%, P = .02). Of note, women had higher unadjusted TLR rates compared with men at 1 year; however, female sex was not an independent predictor of TLR (odds radio [OR], 1.72; 95% confidence interval [CI], 0.68 to 4.37; P = .25). A pooled analysis from four randomized sirolimus versus BMS trials was done to assess for sex differences. In 1748 patients, 497 of whom were women, sirolimus-eluting stents were associated with a significant reduction in the rates of in-segment binary restenosis in women (6.3% vs. 43.8%) as well as in men (6.4% vs. 35.6%), which resulted in significant reduction in 1-year MACE rates ( P < .0001). A pooled analysis of 11,557 women in 26 trials showed decreased mortality, MI, in-stent thrombosis, and TVR in those treated with a DES versus a BMS. In addition, a significant benefit was found with newer-generation over early-generation DESs, including a lower risk of stent thrombosis at 12 months. With respect to contemporary-generation, everolimus-eluting stents, women experience similar risk of 1-year MACEs (death, MI, TVR) but have higher adjusted risk of recurrent ischemic events related to nonstent-related MIs compared with men.

Few sex-based studies on the efficacy of coronary atherectomy and adjuvant devices exist. Although directional coronary atherectomy (DCA) is no longer used, from a historical perspective, it appears to have been associated with lower procedural success and more bleeding complications in women. Likewise, laser atherectomy with the excimer laser catheter was also associated with higher coronary perforation rates and increased morbidity in women. Despite this demonstration, newer atherectomy techniques such as orbital atherectomy have not shown an increased rate of in-hospital or 30-day MACEs compared with men, despite higher baseline risks such as smaller vessels and older age. Female sex is an independent risk factor for TVR after modern, coronary brachytherapy with beta radiation for resistant DES in-stent restenosis (ISR). Limited sex-specific data on rotational atherectomy, cutting or scoring balloon angioplasty, extraction atherectomy, or gamma brachytherapy are available. In smaller studies, sex has generally not been found to be an independent predictor of complications on the efficacy of these devices as a whole, although women have historically been underrepresented in earlier studies of adjuvant device therapies.

Sex Differences in Lesion Subsets

Limited data exist on sex-based outcome differences for PCI by coronary lesion subsets as the primary trial and registry data for efficacy and safety of chronic total occlusions (CTOs), left main coronary disease (LM), and saphenous vein graft (SVG) interventions has historically underrepresented women. Older data indicated the possibility of higher MACEs in women undergoing PCI for CTOs, but these data were acquired between 1998 and 2007, after which techniques and understanding of CTO-PCI improved considerably. More recent retrospective, single-center data demonstrate no discernable differences in procedural success and complication rates. Men are much more likely to undergo CTO-PCI in published data. Data on unprotected LM PCI of 2328 patients from the IRIS-MAIN registry demonstrated that ostial left main and ACS presentations of LM disease were more common in women, and that subsequent TVR was significantly higher in women than men (8.8% vs. 5.7%, P < .05). Women and men had similar frequency of the composite primary end point of all-cause death, MI, or cerebrovascular accident. Sex appears to be a significant predictor of outcomes after SVG PCI. Women have higher 30-day cumulative mortality compared with men (4.4% vs. 1.9%, P = .02) but with notably higher incidence of vascular complications and postprocedural acute renal failure that may drive some of this effect.

Sex Differences in Acute Coronary Syndrome

It is well known that the presentation, pathophysiology, diagnosis, treatment, and outcomes of ACSs differ among men and women. Although women usually present with typical symptoms of ACS, the frequency of atypical presentations of ACS is increased as compared with men. Women typically have higher Killip class and longer prehospital delays when presenting with ACS. Women with suspected ACS are less likely than men to have obstructive or extensive epicardial coronary artery disease (CAD) and are more likely to have either a noncardiac cause or cardiac causes other than obstructive epicardial CAD. Despite this, women with NSTE-ACS with no apparent obstructive epicardial disease still have a 2% 30-day mortality. In fact, women of all ages have higher rates of in-hospital and long-term complications after NSTE-ACS than men including heart failure, cardiogenic shock, acute renal failure, recurrent MI, stroke, readmissions, and bleeding and vascular complications. Data from more than 450,000 patients in the British Cardiovascular Intervention Society (BCIS) and Swedish Coronary Angiography and Angioplasty Registry (SCAAR) between 2007 and 2011 demonstrate significantly higher 30-day and 1-year mortality rates in women compared with men for both non–ST-elevation MI (NSTEMI) and STEMI. After multivariate regression, female sex was an independent predictor of all-cause mortality at 30 days and 1 year. Further large registry data indicate higher in-hospital mortality for women with STEMI but not NSTEMI. Women are also more likely to report preindex psychiatric symptoms including anxiety and depression. Of pathobiologic interest, women who present with NSTE-ACS are more likely to have elevated C-reactive protein (CRP) and brain natriuretic peptide (BNP), whereas men are more likely to have elevated creatine kinase MB (CK-MB) and troponin. Surprisingly, sex differences are apparent in acute MI plaque morphology as well. Autopsies reveal more plaque erosion than plaque rupture in women after fatal MI compared with men ( Fig. 9.1A and B ). In addition, women appear to have more distal microvascular embolization compared with men during fatal MI.

Women who present with an MI are less likely to undergo primary angioplasty within 90 minutes or to receive pharmacologic treatment on admission and are also less likely to be on evidence-based secondary prevention medical treatment upon discharge. In numerous publications, median prehospital delays ranged from 1.8 to 7.2 hours for women versus 1.4 to 3.5 hours in men. In the HORIZONS-AMI trial, symptom-onset-to-balloon time was longer, but this delay was largely driven by late arrival at the hospital. Delays are partly due to the higher frequency of atypical presentations. Overall, women monitored by the National Registry of Myocardial Infarction (NRMI) were more likely than men to present without chest pain, particularly if younger. Women aged younger than 45 years were 30% more likely to present without chest pain than men of similar age. This is an important discrepancy because the nature of presentation for ACS also prompts downstream diagnostic testing such as electrocardiographic (ECG) and biomarker testing, and the lack of symptoms may contribute to delays in diagnostic clarification even when women present to the hospital earlier in their course. Importantly, in studies of the most recent, high-sensitivity troponin assays, which improve diagnosis in both men and women, establishing sex-dependent thresholds doubles the diagnosis of MI in women without affecting the diagnosis rates in men. Women diagnosed by these sex-specific thresholds were notably at a higher risk for death or recurrent MI at 12 months in the same study. .

In 2005, the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) investigators published data on sex differences in patients with NSTEMI from a large registry of more than 35,000 patients, of which 41% were women. They found that women were less likely to receive guideline-based therapies such as heparin (adjusted OR, 0.91; 95% CI, 0.86 to 0.97) at presentation. Moreover, women were less likely to undergo diagnostic left heart catheterization (adjusted OR, 0.86; 95% CI, 0.82 to 0.91) or PCI (adjusted OR, 0.91; 95% CI, 0.86 to 0.96). The CRUSADE registry confirms the unfortunate presence of continued treatment disparities between men and women. Another study that used the American College of Cardiology (ACC) NCDR looked at sex differences among patients with ACS (both NSTEMI and STEMI) and again showed disparities in treatment. Of 199,690 patients, despite fewer high-risk criteria, the 55,691 women had greater in-hospital complications. For example, although the adjusted mortality among women and men was similar (OR, 0.97; 95% CI, 0.88 to 1.07; P = .52), women had higher rates of CHF (OR, 0.80; 95% CI, 0.69 to 0.92; P = .002), bleeding (OR, 0.55; 95% CI, 0.52 to 0.58; P < .01), and cardiogenic shock (OR, 0.82; 95% CI, 0.75 to 0.89; P < .01). Moreover, they found that women were less likely to receive aspirin (OR, 1.16; 95% CI, 1.13 to 1.20; P < .01) at admission and were less likely to be discharged on statins (OR, 1.10; 95% CI, 1.07 to 1.13; P < .01) or aspirin (OR, 1.17; 95% CI, 1.13 to 1.21; P < .01). Older age of female patients, symptom differences, and delay in presentation after acute MI have been suggested as possible explanations. Although these factors may explain initial treatment differences, they do not explain treatment disparities once the diagnosis has been made. These findings call for significant improvements in the care of ACS patients and highlight the importance of continued investigations into perceptual barriers that contribute to these differences.