Impact of Gender on In-Hospital Outcomes following Contemporary Percutaneous Intervention for Peripheral Arterial Disease

Impact of Gender on In-Hospital Outcomes following Contemporary Percutaneous Intervention for Peripheral Arterial Disease
Impact of Gender on In-Hospital Outcomes following Contemporary Percutaneous Intervention for Peripheral Arterial Disease
Impact of Gender on In-Hospital Outcomes following Contemporary Percutaneous Intervention for Peripheral Arterial Disease
Impact of Gender on In-Hospital Outcomes following Contemporary Percutaneous Intervention for Peripheral Arterial Disease
Impact of Gender on In-Hospital Outcomes following Contemporary Percutaneous Intervention for Peripheral Arterial Disease
Impact of Gender on In-Hospital Outcomes following Contemporary Percutaneous Intervention for Peripheral Arterial Disease
Impact of Gender on In-Hospital Outcomes following Contemporary Percutaneous Intervention for Peripheral Arterial Disease

Akio Kawamura, MD, Thomas C. Piemonte, MD, Richard W. Nesto, MD, Seth D. Bilazarian, MD, Nabila S. Riskalla, RN, Manish S. Chauhan, MD

Women with coronary artery disease (CAD) are known to have a higher prevalence of co-morbidities than men, including advanced age, hypertension, diabetes and concomitant non-cardiac disease. Female gender has been shown to be an independent risk factor for morbidity and mortality after coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI),1,2 although this gender difference is diminishing with improvement in new techniques, technology advancements and pharmacologic treatments.3–5

Peripheral arterial disease (PAD) is a subclinical marker of CAD and is equally prevalent in men and women over age 40.6 Women undergoing surgery for PAD have a higher risk of perioperative myocardial infarction (MI), vascular complications and bleeding.7–9 Percutaneous peripheral arterial intervention (PPAI) has emerged as an effective and less invasive alternative to surgical therapy, however, data on gender differences on outcomes of PPAI for PAD, especially in the stent era, are limited.

The purpose of this study was to assess the gender differences in the characteristics and in-hospital outcomes of patients undergoing PPAI for PAD in a single center.

Patient population.
We analyzed data on 268 consecutive patients who underwent PPAI for PAD (excluding carotid angioplasty, endovascular aortic aneurysm repair, or concomitant coronary intervention) in the cardiac catheterization laboratory between October 2001 and January 2004 at a single center. All procedures were performed by 3 interventional cardiologists experienced in peripheral endovascular interventions.

Procedure. Arterial access was obtained via the femoral or brachial approach for all procedures. Percutaneous procedures were performed using rheolytic thrombectomy, balloons or stents, with distal protection device use at the discretion of the operators. Anticoagulation was achieved using either weight-adjusted heparin or bivalirudin to achieve the activated clotting time (ACT) between 250–300 seconds. Femoral arterial sheaths were removed either manually when the ACT was < 180 seconds, or using an approved arteriotomy closure device such as The Closer™ (Perclose Inc., Redwood City, California) or Angio-Seal™ (St. Jude Medical Inc., St. Paul, Minnesota) after selective femoral arteriography confirmed the appropriate insertion site and size of the common femoral artery. All patients with clinical suspicion of a false aneurysm, arteriovenous fistula and retroperitoneal hemorrhage were subjected to ultrasound imaging of the femoral artery or an abdominal computed tomography scan. The NCDR database and the patients’ charts were used for data collection.

Definitions. Lesion success was defined as attainment of < 30% diameter stenosis by visual estimation at post-procedure angiography. Procedure success was defined as lesion success without any major adverse events including death, MI, stroke, transient ischemic attack (TIA), and emergent surgery. MI was defined as new significant Q-waves in 2 or more contiguous electrocardiography leads (QMI), or elevation in creatine kinase (CK) or CK-MB levels to more than 3 times the upper limit of normal in the absence of new Q-waves (non-QMI). Stroke was defined as new neurologic deficit lasting ? 24 hours, and transient ischemic attack (TIA) as new neurologic deficit lasting < 24 hours. Contrast nephropathy was defined as an increase of more than 25% from the baseline value in the serum creatinine concentration at any point during admission for patients who were not on hemodialysis. Vascular complications were defined as pseudoaneurysm formation, arterio-venous fistula requiring surgical repair, or infection at the access site. Major bleeding was defined as intracranial, gastrointestinal, or retroperitoneal hemorrhage, or clinically overt blood loss resulting in a decrease in hemoglobin > 3 g/dl, any decrease in hemoglobin > 4 g/dl, or transfusion of 2 or more units of packed red blood cells. Minor bleeding was defined as clinically overt bleeding that did not meet the criteria for major bleeding. These adverse events were adjudicated by an independent observer.

Statistical analysis. Quantitative data are presented as mean value ± 1 SD, and qualitative data as frequencies. Continuous variables were compared using unpaired Student’s t -tests or the Mann-Whitney U-test. Categorical variables were examined by the chi-square test or Fisher’s exact test. All probability values are two-tailed, and a p-value < 0.05 was considered statistically significant. To identify predictors of hemorrhagic complication, univariate variables with a p-value < 0.2 were entered into the multivariate logistic regression models. Statistical analysis was performed with Stat View 5.0 (Abacus Concepts Inc., Berkley, California).

Baseline clinical and lesion characteristics (Tables 1 and 2).
Of the 268 patients, 122 (45.5%) were women. A total of 346 vessels (women: 159, men: 187) and 405 lesions (women: 184, men: 221) were treated. Prior history of coronary intervention was more prevalent in men than women. Current smokers were more frequently found in women. Body mass index was similar between women and men, but women had smaller body surface area. For patients who had lower extremity arterial interventions, the left side ankle:brachial index was lower in women than men (0.58 ± 0.22 versus 0.70 ± 0.19; p = 0.003). Lesion characteristics were similar, except upper extremities interventions were performed more frequently in women than in men.

Procedural characteristics (Tables 3 and 4). Mean arterial sheath size and use of a closure device were similar between the two groups. For patients with infrainguinal disease, the anterograde femoral approach was less frequently performed in women than in men (8.8% versus 27.8%; p < 0.05). Stents were used in 79.5% of women and 70.5% of men (p = 0.09). No differences were observed in the use of antiplatelet agents or anticoagulation therapy. Glycoprotein (GP) IIb/IIIa inhibitors were used in 2 patients (0.7%) for acute flow reduction in the treated artery during the procedure. Thrombolytic agents were not used for any procedures.

In-hospital outcomes (Table 5). There were no significant differences in the in-hospital outcomes in terms of lesion success, procedure success, death, stroke or TIA, and contrast nephropathy in women compared with men. Hemorrhagic complications occurred more frequently in women than men (7.4% versus 0.7%; p = 0.006).

All hemorrhagic events occurred at the access site or were retroperitoneal in location. The blood transfusion rate was also significantly higher in women (6.6% versus 0.7%; p = 0.013). Women with an arteriotomy closure device had a lower incidence of bleeding compared to women in whom no closure device was used, although it did not reach statistical significance (3.8% versus 10.1%; p = 0.3). Similarly, no significant difference was noted with the use of arterial closure devices in men (0% versus 2.2%; p = 0.53).

Predictors of hemorrhagic complications (Tables 6 and 7). Univariate predictors of hemorrhagic complications with a p-value < 0.2 were female gender, pre-procedure thienopyridine use, and the use of GP IIb/IIIa inhibitors during the procedure. Multivariate logistic regression analysis showed that female gender was the only significant predictor of hemorrhagic complications (odds ratio = 12.2, 95% confidence intervals 1.39–111.1; p = 0.024).

This study demonstrates that PPAI using contemporary devices and pharmacologic treatments can be performed in women with similar success rates as in men, albeit with over a ten-fold higher risk of hemorrhagic complications compared to men.

Patients undergoing PCI and PPAI have similar risk factors such as hypertension, diabetes and smoking.6 Compared to men, women undergoing PCI are noted to be older and have a higher prevalence of comorbidities such as diabetes. In spite of the similar extent of CAD and the procedural success rate compared to men, women have a higher incidence of vascular and bleeding complications.10 This difference has traditionally been explained by smaller body surface area, smaller vessels and older age. Furthermore, patients with PAD undergoing PCI have almost a two-fold higher incidence of bleeding complications.11 Consequently, women undergoing PPAI with or without CAD may constitute a high-risk population for vascular and bleeding complications.

Data on gender differences in outcomes for patients undergoing PPAI who have similar atherosclerotic disease processes and comorbidities are limited, especially in the contemporary device era. Prior angioplasty studies for peripheral arterial interventions predominantly using balloons showed similar success rates between men and women, but with a higher risk for bleeding complications in women.12,13 In these studies, stent and arterial closure device use was minimal, and heparin was predominantly used as an anticoagulant agent.

Patients in our study had several cardiovascular and medical comorbidities such as diabetes, renal insufficiency, along with significant PAD, placing them in a higher risk category for any percutaneous procedure. The peripheral arterial interventions involved several territories, requiring vascular access via different routes, and many devices including stents, in over 70% of patients. Although women had smaller body surface area, a surrogate for smaller vessel size, women had similar lesion and procedural success rates compared to men, which may be attributable to improvement in techniques and devices. In-hospital outcomes were similar between the two groups, although women had over a ten-fold higher incidence of bleeding complications compared to men, a finding no different than patients undergoing PCI for CAD.4,10,14–17

Hemorrhagic complications. Vascular and hemorrhagic complications are major causes of morbidity, increased cost after catheter-based interventions, and even death.18 The excessive risk of major bleeding in women in our study was in line with previous studies of PPAI as well as PCI.12–14,17,19 Although the cause of heightened susceptibility to hemorrhagic complications in women is still unclear, several reasons including older age, smaller vessels, sheath size and differing pharmacokinetics of antiplatelet and anticoagulant agents have been proposed.15,16,18,20,21 A prior study has shown prolonged partial thromboplastin time for women given heparin, even after weight-adjusted dosing.21 Less aggressive anticoagulation, or use of a direct thrombin inhibitor, may decrease the risk of bleeding complications. The safety profile of bivalirudin was shown in the recently-published APPROVE trial.22 In coronary intervention with GP IIb/IIIa inhibitors, on the other hand, a significant interaction between gender and access site bleeding has been suggested.15,16 Because the overall use of GP IIb/IIIa inhibitors was limited in our study (0.7%), we cannot assess the effect of these agents in PPAI. The role of GP IIb/IIIa inhibitors in PPAI needs to be evaluated in larger studies.

Interestingly, arterial closure devices were used in almost 60% of our patients after PPAI. Although it has been suggested that women may be at significantly higher risk than men for access site complication with the use of hemostasis devices, such a relation or any protective effect of these devices from hemorrhagic complications were not noted in our study.23,24

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