Cardiovascular Interventions in Women: Are All Therapies Created Equal?

Luis Gruberg, MD, FACC

Disclosures

June 09, 2006

Editorial Collaboration

Medscape &

"There is certainly a void of knowledge as to how we can optimize treatment for our female patients with CVD. More trials are an absolute necessity to clarify the best therapeutic alternatives for this important group of patients."

Introduction

More than 71 million Americans have 1 or more types of cardiovascular disease (CVD).[1] CVD affects men and women at similar rates (34% of each group), but the rate of mortality is higher in women than in men (53% vs 47%).[1]

Similar disparities have been noted among victims of myocardial infarction (MI). Each year, more than 1 million people suffer an MI; 50% of cases are fatal, and many of these deaths occur within 1 hour of symptom onset. Data from the Framingham Heart Study show that more women than men will die within 1 year of having an MI (38% vs 25%).[1] In addition, in-hospital mortality after elective or emergency percutaneous coronary intervention (PCI) is higher in women, while late mortality is similar to that of male patients.[2]

The difference in outcomes between the sexes has been attributed to a complex interplay of many factors, including the underutilization of practice guideline-recommended therapies.[3] For example, more than 1.2 million PCI procedures are performed annually in the United States, but only an estimated 33% are performed in women. Data from the 2002-2003 Euro Heart Survey show that, in addition to being less likely to undergo revascularization, women are also less likely to receive aspirin or statins. These findings are troubling, given that women tend to have a higher incidence of comorbid conditions at baseline, which also complicates outcomes. Other attributable factors include that, compared with men, women: are more likely to have a delayed onset of disease; usually present later and at an older age; tend to be of smaller stature; and noninvasive testing is associated with a lower predictive value.

Nevertheless, contemporary trials and registries have shown that after adjustment for these factors, gender differences are virtually eliminated, dismissing the idea that mortality risk is sex-specific.

Despite the fact that public service campaigns, such as those initiated by the American Heart Association and the American College of Cardiology, have increased the awareness of CVD risk in women among the general population,[4] a recent survey of physicians found that fewer than 1 in 5 physicians were aware that CVD was the leading cause of death in women.[5]

Currently, there are only limited data on outcomes in women following interventional procedures. While heavily underrepresented in large clinical trials, subgroup analyses focusing on the outcomes of women enrolled in these large studies will help to increase awareness in the medical community, help facilitate care for our female patients, and rule out the potential gender bias in revascularization techniques. A session regarding women and percutaneous vascular interventions was held at the EuroPCR 2006 meeting. Below are brief summaries from each of the presentations.

"Drug-Eluting Stents: Have They Improved Outcomes?"

Presenter: Eberhard Grube, MD (Heart Center Siegburg, Germany)

Drug-eluting stents (DES) have significantly reduced restenosis after stent implantation in the coronary arteries. Target lesion revascularization (TLR) rates have dropped from an average of 20% to as low as 6%. For this reason, 90% of all stents currently deployed in the United States are DES, and similar trends are seen throughout the world.

Despite the widespread use of DES and its proven effectiveness, previous studies have suggested that there are marked differences in the diagnosis, treatment, and subsequent outcomes between men and women with coronary heart disease. But subanalyses of the drug-eluting trials suggest otherwise.

For example, the overall results of the SIRIUS trial[6] found that use of the sirolimus-eluting stent was associated with a significantly lower rate of TLR as compared with a bare-metal stent. A subgroup analysis of the SIRIUS trial that compared outcomes by gender suggests that once women are referred for cardiac catheterization, revascularization rates are similar to those in men. Results of the analysis showed that the overall findings of the main trial were not influenced by gender; use of the sirolimus-eluting stent equally benefitted men and women in the trial (Figure 1).

Figure 1. SIRIUS: sirolimus-eluting stent vs control -- target lesion revascularization rates by gender.

Similar results were observed in a subgroup analysis of the TAXUS II study, in which the incidence rates of TLR and late loss were significantly reduced in patients randomized to the paclitaxel-eluting stent (vs control), regardless of gender (Figure 2). Although it is too early to make any definitive conclusions, an analysis of the TAXUS IV trial suggests that use of the paclitaxel-eluting stent in women was associated with lower rates of TLR and target vessel revascularization (TVR) than those seen in men who received the same treatment (Figure 3).

Figure 2. TAXUS II: paclitaxel-eluting stent vs control -- target lesion revascularization (TLR) and late loss by gender.
Figure 3. TAXUS IV: target lesion revascularization (TLR) and target vessel revascularization (TVR) in patients treated with the paclitaxel-eluting stent by gender.

So, do DES perform equally well in both male and female patients? We can't say for sure from the data that are currently available, but these subgroup analyses do suggest that the use of DES is associated with favorable long-term results, regardless of gender differences.

"Acute Myocardial Infarction: Do Women Benefit From Primary Angioplasty?"

Presenter: David Antoniucci, MD (Azienda Ospedaliero-Universitaria Careggi, Florence, Italy)

Data from the National Registry of Myocardial Infarction two (NRMI-2)[7] have shown that the rate of in-hospital mortality is twice as high in younger women with MI as in their male counterparts. This difference diminishes with age, however, and the risk then becomes higher in older men.

In the first and second Primary Angioplasty in Myocardial Infarction (PAMI-1 and PAMI-2) trials, there was no difference in adjusted mortality between men and women. However, in the Stent-PAMI trial, there was no beneficial effect of stents (vs plain balloon angioplasty) in women (12% vs 15.5%, respectively; P = .47). Furthermore, in this study, female gender was a strong predictor of 1-year mortality (OR 2.24, CI 1.07-4.69, P = .032). Whereas gender was not a predictor of 1-year mortality in the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial, it was a predictor of major adverse cardiac events (HR 1.64, CI 1.24-2.17, P = .0006).[8]

In an analysis of the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) registry,[9] investigators initially found that in-hospital mortality was higher in women than in men. However, after adjusting for differences in patient demographics and treatment approaches, no significant difference was observed between the 2 groups.[10].

Overall, women tend to have a higher incidence of comorbid conditions at baseline, which is associated with higher mortality rates when compared with male counterparts. However, the benefit of early PCI in the acute phase of MI is similar in women and men and, thus, any potential referral bias for PCI based on gender should be avoided.

"Angioplasty or Surgery for Coronary Heart Disease: What Is Best for a Woman?"

Presenter: Vassilios Voudris, MD (Onassis Cardiac Surgery Center, Athens, Greece)

Once women are referred for catheterization, revascularization rates and practices are similar to those seen in men. However, women who undergo coronary artery bypass surgery (CABG) fare worse than men who undergo the same procedure, with higher rates of in-hospital mortality and cardiac readmissions. In part, these results may be attributed to the fact that women are usually older, smaller in stature, receive less mammary grafts, have a lower incidence of complete revascularization, and usually undergo the procedure due to acute coronary syndromes (ACS).

Data from the second Arterial Revascularization Therapies Study (ARTS II), analyzed according to gender, showed similar outcomes between men and women with multivessel disease treated with a sirolimus-eluting stent (Figure 4). In addition, in ARTS II, outcomes in female patients treated with the DES were significantly better than those seen in female patients who underwent CABG in the ARTS I trial.

Figure 4. ARTS II: outcomes of patients treated with sirolimus-eluting stent by gender.
CVA = cerebrovascular event; MACCE = major adverse cardiac and cerebrovascular event; MI = myocardial infarction

These results demonstrate that PCI can be performed safely and effectively in women, even in complex settings, and the procedure can save lives and prevent future heart attacks, not just relieve symptoms. Currently, women undergoing CABG have higher early mortality rates, but excellent late outcomes following CABG surgery. Randomized trials are needed to clarify the best revascularization procedure in women.

"Gender Differences in the Use of Adjunctive Medical Therapies During Percutaneous Coronary Intervention"

Presenter: Alexandra J. Lansky, MD (Columbia Medical Center, New York, NY)

Women are more likely to have aspirin resistance and also face an increased risk of bleeding and vascular complications after PCI in any setting. Although no sex-specific data exist for the use of thienopyridines, recommendations are similar for men and women.

In women with ACS, studies such as the Treat Angina with Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy (TACTICS-TIMI 18)[11] showed that treatment with an early aggressive approach yielded better outcomes than conservative treatment (although the benefit was not as significant as in male patients). By contrast, among women, the Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II)[12] study found that an aggressive approach (vs conservative treatment) was associated with worse outcomes, and the results of the Randomized Intervention Trial of Unstable Angina (RITA 3)[13] failed to show a difference between the 2 approaches in women. Among male patients, however, all 3 studies showed a benefit from an early invasive approach.

Regarding the use of antiplatelet agents in patients undergoing PCI, a meta-analysis[14] of more than 6500 patients (27% female; 73% male) from 3 trials showed that the benefit of the glycoprotein IIb/IIIa inhibitor (GPI) abciximab in preventing death, MI, or TVR was independent of gender. However, female patients had a significantly higher rate of bleeding complications with abciximab.

An analysis of the CADILLAC trial[8] found that women with acute MI who underwent primary stenting with or without the addition of abciximab had significantly lower rates of MACE and TVR at 12 months compared with women treated with angioplasty with or without abciximab treatment. The addition of abciximab to primary stenting also significantly reduced the rate of TVR at 30 days compared with stenting alone (P = .03) and was not associated with any significant increases in the bleeding complications. But the early benefit was no longer significant at 1 year. There was no significant survival benefit of one treatment strategy over another.

Similar findings were noted among women in the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events II (REPLACE-2) trial, which randomized patients undergoing elective or urgent PCI to use of the direct thrombin inhibitor, bivalirudin, plus provisional GPI use or heparin plus planned GPI use. In women, the use of bivalirudin plus provisional GPI use was not inferior to the use of heparin plus provisional GPI therapy, and there were no differences in incidence of the primary endpoint (composite of death, MI, urgent revascularization, and major in-hospital bleeding complications at 30 days) or in the rate of death at 30 days; the results remained unchanged at 6 months. However, use of bivalirudin plus provisional GPI was associated with significant reductions in the rate of minor and major bleeding complications vs bleeding rates in women treated with heparin plus GPI (Figure 5).

Figure 5. REPLACE-2: bleeding complications in women.

Among women, independent predictors of bleeding were the use of heparin plus GPI. In addition, women had a higher incidence of minor and major TIMI bleeding compared with men, and female gender was found to be an independent predictor of major bleeding complications in patients undergoing PCI (OR 1.61, CI 1.14-2.29, P = .008).

Excess dosing of GPI inhibitors may be responsible for a higher rate of bleeding complications in women. In an observational analysis of the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines?)[15] registry, patients who received an excess dose of GPI had a significantly increased risk of major bleeding. Female gender was an independent predictor of receiving an excess dose. These findings emphasize the need to give careful attention to ensure proper GPI dosing in women in order to minimize bleeding complications.

In conclusion, the results of these subgroup analyses demonstrate that in female patients, the use of anticoagulants during PCI yields similar clinical outcomes to those observed in men. However, female patients are at higher risk of bleeding complications at standard male dosage. Therefore, alterations in the use of these drugs are needed, such that the use of GPI is recommended in women with high-risk ACS but should be avoided in low-risk women. In addition, clinicians may want to consider using a lower dose in women treated with heparin plus GPI. Furthermore, bleeding complications could be reduced 2- to 3-fold in women by using weight-adjusted heparin dosing and earlier sheath removal.

"Is There Any Indication for Carotid Artery Stenting in Women?"

Presenter: Bernhard Reimers, MD (Miro General Hospital, Mirano, Italy)

Stroke is a devastating disease, both for the patient and his or her family. Stroke presentation in women is usually worse than in men. Female patients are usually older, have more in-hospital complications and a longer length of hospitalization stay.[16] Furthermore, previous studies have shown significant anatomical differences in the distribution of atherosclerotic disease between men and women. Whereas men have a larger atherosclerotic plaque area that is usually distributed distal to the carotid bulb in the internal carotid artery, in women, the stenosis is usually more severe and is usually found in the external carotid artery.[17] However, there is no difference in the length of stenosis.

Outcomes following stroke treatment also vary between men and women. For example, women tend to respond better to medical therapy than men do,[18] and while they may have similar outcomes following carotid endarterectomy, women tend to have higher rates of restenosis (17.2% vs 6.3%).[19]

In the North American Symptomatic Carotid Endarterectomy Trial (NASCET),[20] the risk of stroke at 5 years in female patients with a degree of stenosis of 50% to 69% was similar for patients receiving medical treatment and those undergoing carotid endarterectomy, whereas in male patients, carotid endarterectomy was associated with a significant reduction in the risk of stroke relative to medical therapy. Similar results were observed in the Asymptomatic Carotid Surgery Trial (ACST),[21] where the benefits associated with deferred endarterectomy were less pronounced in women than in men. Carotid artery stenting, a less invasive approach than surgical endarterectomy, is also an effective treatment in both men and women. In the Italian/German Carotid Artery Stenting Registry, for example, major stroke, minor stroke, and death rates were similar in men and women (Figure 6).

Figure 6. Italian/German CAS Registry: stroke/death at 30 days.

In summary, despite gender differences in the anatomy of carotid arteries and worse outcomes following stroke in women, the procedural results of carotid endarterectomy and carotid artery stenting are similar between men and women. Unfortunately, men are more likely to undergo endarterectomy and stenting than women are. To reduce the risk of stroke, more women should be referred for invasive treatment. Finally, indications for endarterectomy and carotid artery stenting should be equal for men and women.

Viewpoint

As physicians, we need to remind ourselves that CVD accounts for the vast majority of death in female patients, and affects a higher proportion of female than of male patients. Despite this important statistic, women have been consistently underrepresented in major trials, and the benefits of interventional therapies have yet to be studied solely in women. Instead, the overall findings from trials are applied universally to both men and women.

However, as illustrated by the aforementioned analyses, which are limited by their small sample size, disease presentation and outcomes tend to vary between the sexes. In part, this is attributable to the fact that women usually present later following symptom onset and are older at the time of presentation, and have more risk factors, a smaller body surface area, worse short-term outcomes, and higher rates of periprocedural complications, especially bleeding.

There is certainly a void of knowledge as to how we can optimize treatment for our female patients with CVD. More trials are an absolute necessity to clarify the best therapeutic alternatives for this important group of patients.

References
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  2. Lansky AJ, Hochman JS, Ward PA, et al. Percutaneous coronary intervention and adjunctive pharmacotherapy in women: a statement for healthcare professionals from the American Heart Association. Circulation. 2005;111:940-953. Abstract

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  8. Lansky AJ, Pietras C, Costa RA, et al. Gender differences in outcomes after primary angioplasty versus primary stenting with and without abciximab for acute myocardial infarction: results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. Circulation. 2005;111:1611-1618. Abstract

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  15. Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA. 2005;294:3108-3116. Abstract

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