Gender Differences for Coronary Antio~lastY I - I I

Anita M. Arnold, DO, Matthew J. Mick, MD, Marion R. Piedmonte, MA, and Conrad Simpfendorfer, MD

To detemdne if diirences in early and late out- come after m&tplasty were lwlated to gender or body surface area, 6,000 Bive patients (1,274 women and 3,726 men) were studied. Baseline vatiaMeq procedural outcome, and hng-twm and event-fme survival were B. Baseline variables included age, history of hyper- tension, diabetes mellitus, heart failure, my- dial infarction, p&r angloplasty or bypass surgery, familial comuwy disease, Canadian heart dassiflcation, extent of angioplasty, left ventflcular function, and body surface area. Overall and evcmt-fme survival (freedom from irr fa=tim repeat -stWasty, bw- -@w d death)were- at followup. The results showed that, compared with men, women were older (p eO.OOOl), had a higher prevalence of di- abetes (p *O.OOOl), familial colonay di- (P q 0.992), hypertension (p <0.0001), prior infarG tion (p q O&04), and more involvement of the anterior deecendi~ awry (p = 0.017). whereas men had similar extents of angioplasty and worse left vent&&u function (p = 0.012), women more often had unstable anghm (p *0&001).Thasuccessrateswere similar,yet women had a higher procedural mortality (1.1% women, 0.3% men, p = 0.001). when co?Tected for body surface area, however, women were at no greater risk thm men. Followup was corn- pktefor97.4%ofpatients(mean4 + 2years). Eve survival was signiiicantly better in womsn, even after correcting for body surface area.Menwereathi@kerriskforlatedeathand repeat an@oplasty on followup. It is concluded thatwomenarenotathiirli!skforprocedunc related mortalii when compared with men, and their overall and eve&free survival surpassed that of men. In this respect, the Ygender dii ence” favors women.

(Am J Cardlol1994;74:18-21)

From the Departments of Cardiology and Biostatistics and Epidemiol- ogy, Cleveland Clinic Foundation, Cleveland, Ohio. Manuscript re- ceived August 2,1993; revised manuscript received December 3,1993, and accepted December 5.

Address for reprints: Conrad Simpfendorfer, MD, The Cleveland Qmic Foundation, Department of Cardiology, Desk F-25,9500 Euclid Avenue, Cleveland, Ohio 441955066.

C onsiderable interest has been generated concem- ing health issues affecting women.*,2 The federal government has determined that heart disease is

the major cause of death for women in the United States.3 Despite this, most of the data regarding coronary disease are derived from studies in men. Differences in outcome have been reported after coronary bypass surgery.4-7 These differences have been presumed to be gender-re- lated, or perhaps attributable to a size differential be- tween the sexes. Women have been considered to be at higher risk for coronary angioplasty than men, as re- ported in the National Heart, Lung, and Blood Institute regisQ8

This study was undertaken to examine differences in early and late outcome of men and women undergoing coronary angioplasty, and to determine if the gender dif- ference was correlated with body surface area. When- ever gender was significantly related to outcome, we then corrected for body surface area to determine if the dif- ferences were gender- or size-related.

METllODS The first 5,000 consecutive patients undergoing elec-

tive coronary angioplasty from December 1980 to September 1988 were identified using a computerized database. Angioplasty for an acute myocardial infarction was excluded from analysis. The first angioplasty per- formed at our institution was used as the initial proce- dure; subsequent procedures were termed “cardiac events” during follow-up. Incomplete data were obtained by review of the medical record. All other data were prospectively collected. The following variables were retrospectively analyzed: age, gender, history of hyper- tension, diabetes mellitus, congestive heart failure, myo- cardial infarction, prior angioplasty or bypass surgery, familial coronary atherosclerosis, and Canadian heart classification. Lesion characteristics were not analyzed, but the angioplasty vessel, left ventricular function, and procedure outcome were analyzed.

Definitions: Left ventricular function was graded qualitatively in 2 groups of patients identified: those with normal or mild left ventricular dysfunction, and those with moderate or severe dysfunction. Canadian Heart Association angina1 class was defined as originally pro- posed by Campeau.g Unstable angina was detined as new onset angina (within 8 weeks), rest angina, or progres- sive angina. Angiographic success was detined as >20% reduction in stenosis with residual stenosis 40% of the luminal diameter. Clinical success was detined as an- giographic success not associated with a complication. In-hospital complications were repeat angioplasty, myo- cardial infarction, bypass surgery (elective during the same hospitalization or emergent), or death.

Followup: Follow-up data were obtained by repeat visits, or telephone contact with the patient or referring

I.8 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 74 JULY 1,1994

TABLE I Baseline Characteristics

Characteristic Women (n = 1,274) Men (n = 3,726) p Value

Age (mean + SE years) Diabetes mellitus Multivessel angioplasty Familial coronary disease History of congestive failure Canadian heart class III/IV Hyperlipidemia Hypertension Prior bypass surgery Prior myocardial infarction Prior angioplasty LAD involvement LV dysfunction (med./severe) Unstable angina

61.5 + 0.26 20%

14.6% 56.5%

7.4% 58.0% 26.3% 57.5%

10% 31.5%

2.6% 54.4%

9.2% 58.6%

57.1 + 0.15 11.6% 15.9% 51.4%

5.3% 42.0% 26.5% 39.8% 14.6%

36% 3.2%

50.5% 11.8% 47.8%

<0.0001 <0.0001

0.39 0.002 0.007

<0.0001 0.57

<0.0001 <0.0001

0.004 0.34 0.017 0.012

<0.0001

LAD = lefl anterior descending coronary; LV = left ventricle; mod. = moderate

TABLE II In-Hospital Events

Event Women Men p Value

Overall events 9% 7% 0.023 Failed angioplasty 6.4% 6.7% 0.81 Bypass surgery 5.0% 4.5% 0.38 Myocardial infarct 0.4% 0.4% 0.96 Death 1.1% 0.3% 0.001+

‘When corrected for body surface area, p = 0.24.

physician. Follow-up was complete for 97.4% of pa- tients. Of the patients with incomplete data, 78 (1.6%) were lost to follow-up, and 52 (1%) had no follow-up after discharge (most were foreign nationals). Survival was determined from the time of procedure to the time of death from any cause. Event-free survival was delined as survival without repeat angioplasty, bypass surgery, myocardial infarction, or death. The survival time of pa- tients with multiple events was calculated from the ini- tial procedure to the lirst event. The cause of death in patients who died was determined as cardiac or noncar- disc.

Statlsticri: (X-square tests were used to compare categorical baseline variables, and t tests for continuous variables. The association between the anatomic and clinical variables with respect to in-hospital events was examined using logistic regression models. Univariate analyses followed by forward stepwise selection to build a multivariate model were conducted, with a p value of 0.05 as the criterion for entry into the model. The asso- ciation between the variables and long-term end points were assessed using univariate and multivariate Cox pro- portional-hazards regression models using the same for- mat as previously described.‘O In all analyses for either in-hospital or long-term events, if gender was signifi- cantly related to the end point, a new model was fit con- taining all variables previously found significant as well as body surface area. We then assessed whether the sig- nificance of gender still held after adjusting for the nat- ural differences between men and women with respect to body surface area.

RESULTS Of the lirst 5,000 coronary angioplasties, 1,274 (25%)

procedures were performed in women, and 3,726 (75%) in men (Table I). The women were older (p <O.OOOl) (mean age 61.5 years [SE 0.26, range 31 to 851). The mean age in men was 57 years (SE 0.15, range 27 to 88). More women presented with Canadian heart class III or IV (p <O.OBOl). More women were diabetic (p <0.0001), had familial coronary artery disease (p = 0.002), and hypertension (p ~0.0001). Men more often had previous bypass surgery (p <O.OOOl) or myocardial infarction @ = 0.004). The prevalence of moderate or severe left ventricular dysfunction was more frequent in men (p = 0.012). More women had angioplasty involv- ing the left anterior descending artery (p = 0.017). There was no difference in angiographic or clinical success rates between women and men.

lmtal even& Overall, women had a higher in- hospital event rate than men (9% women, 7% men; p = 0.023). The variables analyzed were repeat angioplasty, bypass surgery, myocardial infarction, and death (Table II). The only statistically significant variable was proce- dure-related death, which occurred more often in women than in men (1.1% for women, 0.3% for men; p = 0.001). Multivariate analysis for risk factors related to in-hospi- tal events for the 5,000 patients found that women were at higher risk for in-hospital events than men. No other factor was found to significantly increase the risk of in- hospital events (p = 0.02; risk ratio [RR] for female gen- der, 1.31; 95% contidence interval [CI], 1.04 to 1.65) (Table III). However, once a correction was made for body surface area, women were no longer at higher risk than men, eliminating the so-called “gender difference” for procedural mortality (RR 1.08, CI 0.81 to 1.45, p = 0.59).

Followup: Follow-up was complete in 97% of pa- tients. The median follow-up time was 4 years (range 0.3 to 10.4) and did not differ between women and men. At the time of the study, 93% of patients were alive; 1,831 (40%) patients had an event during follow-up. By multi- variate analysis, an attempt was made to determine which baseline variables were associated with a decreased event-free survival. These factors are listed in Table IV

GENDER DIFFERENCES FOR ANGIOPIASTY 19

r TABLE III Risk Factors for In-Hospital Events

Univariate Factor RR 95% Cl p Value

A@ 1.25 0.99-i .58 0.1 Hypertension 0.92 0.74-l .14 0.43 Canadian heart class 1.11 1.0-l .23 0.04 Diabetes mellitus 0.88 0.62-1.19 0.36 History of heart failure 1.19 0.78-l .82 0.42 Hyperlipidemia 0.99 0.78-l .26 0.94 Prior bypass 0.89 0.64-l .23 0.46 Prior infarct 1 .Ol 0.81-l .26 0.92 Prior angioplasty 0.6 0.28-l .28 0.15 LAD involved 0.86 0.7-l .07 0.17 LV dysfunction (med./severe) 0.97 0.69-l .37 0.88 Women 1.31 1.04-l .65 0.02 Unstable angina 1.25 1.01-1.55 0.03

Multivariate Women 1.31 1.04-l .65 0.02

Adjusted for body surface area Women 1.08 0.81-l .45 0.59 Body surface area 0.5 0.26496 0.03

Cl = confidence interval; LAD = left anterior descending artery; mod. = moderate: RR = risk ratio.

Male gender was a risk factor for decreased event-free survival (RR 1.65, CI 1.21 to 2.25, p = 0.0017).

Given male gender as a risk factor for a lesser event- free survival, late events that occurred more often in men were examined. We therefore examined factors signiti- cantly associated with each end point separately. Men were at signihcantly greater risk, even when correcting for body surface area, for repeat angioplasty (RR 1.24, CI 1.05 to 1.47, p = 0.01) and late death (RR 1.65, CI 1.21 to 2.25, p = 0.0017) than women, but not for myo- cardial infarction or subsequent coronary artery bypass surgery.

DISCUSSION Investigators have sought to delitie clinical and an-

giographic predictors of a favorable early outcome and long-term success regarding myocardial revasculariza- tionii-15 With coronary bypass surgery, women have a higher incidence of incomplete revascularization6J6 and a higher complication rate than men7 These data have been explained, in part, by suggesting that women fared worse because of their smaller body surface area,5,7 al- though survival data suggest no ditference after bypass surgery. l7

w angIoplasty: Attempts have been made to detine clinical and angiographic predictors of procedu- ral and long-term success. 1s-2o In 1985, the National Heart, Lung, and Blood Institute published its registry results which included 705 women (23% of patients).8 Women were older, and had a higher prevalence of class III or IV angina than men. Despite more men having multivessel disease and worse left ventricular function, women had a lower angiographic success rate and more complications. Women had more coronary dissections, 6 times the procedure-related death, and 5 times the mor- tality with emergency bypass surgery. Multivariate anal- ysis indicated that female gender was an independent predictor for lower success and early mortality. When examining size as a variable, the investigators were able

TABLE IV Factors Significant for Event-Free* Survival

Factor RR 95% Cl p Valuet

Age 5 70 years 2.81 2.10-2.16 0.0001 Hypertension 1.47 1.18-1.84 0.0006 Canadian heart class 1.36 1.01-l .25 0.0289 Diabetes mellitus 1.7 1.31-2.21 0.0001 Heart failure 2.35 1.73-3.20 0.0001 Prior bypass 1.64 1.26-2.13 0.0002 Left ventricular dysfunction 2.12 1.62-2.77 0.0001

Male sex 1.65 1.21-2.25 0.0017

‘Event-free survival: freedom from death, myocardial infarction, repeat percutaneous transluminal coronary angioplasty, or bypass surgery.

tThe p values are corrected for body surface area. Abbreviations as in Table III.

to identify a significant inverse linear relation between height and mortality in men, but not in women. Recently, the National Heart, Lung, and Blood Institute examined 546 women who underwent angioplasty, and found more immediate complications and higher procedural mortal- ity in women than in men.21

DeFeyter et a122 examined immediate and late results in 200 patients undergoing angioplasty for unstable an- gina. Female gender was not associated with a higher rate of complications. Ellis et al23 reported female gen- der as an independent predictor of acute occlusion in 4,772 procedures.

Late evemts after angioplaaty: Although there have been reports on the late outcome after angioplasty,*27 few studies directly compare such results between women and men. The National Heart, Lung, and Blood Institute examined late follow-up and found that men had a higher incidence of angiographic restenosis (36% vs 22%, p cO.Ol), repeat angioplasty (18% vs lo%, p <O.Ol), and additional myocardial revascularization (27% vs 18%, p cO.01) than women. Cumulative mortality was also worse for men (2.2% vs 0.3%, p 4.05). Similarly, other inves- tigators have reported that male gender is associated with angiographic restenosis on late follow-up.22y28 In evalu- ating the 2-year outcome after angioplasty in patients with multivessel disease, Ellis et al29 did not rind event-free survival to be inlhtenced by gender.

In this study, female gender predisposed to a less fa- vorable early outcome when compared with men. How- ever, after correcting for body surface area, this was no longer true. On follow-up, even with a higher risk fac- tor profile, their overall and event-free survival surpassed that of men. These data also show male gender is a risk factor after coronary angioplasty for repeat angioplasty. This increased risk was independent of body surface area, suggesting a true gender difference in favor of women for a better long-term, event-free survival.

Stasdy IImItatIons This study attempts to control for 1 variable between women and men, that of body surface area. This study represents a group referred to a tertiary care facility and may not be applicable to alternative pop- ulations. These results are for elective angioplasty and would not apply to angioplasty for acute myocardial in- farction. Also, because of the advances made in technol- ogy since 1985, the outcomes may be different in popu- lations now undergoing angioplasty.

20 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 74 JULY I,1994

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GENDER DIFFERENCES FOR ANGIOPLASTY 21