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SEX DIFFERIENCES IN SURGICAL RISK:
AN ANALYSIS OF STROKES AFTER STIROKE PREVENTION SURGERY
Moira Kassia Kapral
A thesis submitted in conformity with the requirernents for the degree of Master's of
Science, Graduate Department of Community Health, University of Toronto
OCopyright by Moira Kassia Kapral 1998
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Sex DifEerences in Surgicd Risk: An Analysis of Strokes &er Stroke Prevention Surgery
Master's of Science, Department of Comrnunity Health, University of Toronto, 1998
Moira Kassia Kapral
This thesis compared the surgical complications of carotid endarterectomy in men and
women, ushg Ontario administrative data as weU as data fiom two randomized trials. The
administrative database analysis indicated that women were more likely to be
institutionalized &er surgery (odds ratio 1 -39, 95% confidence interval 1-13, 1.72.
P=0.003), and were more likely to have an exiended length of stay (odds ratio 1.20, 95%
confidence interval 1.09, 1.3 1, Pc0.001). The triais database analysis found a trend
towards an increased nsk of perioperative death or stroke in women cornpared to men.
but this was not statistically signincant (odds ratio 1.34, 95% confidence interval 0.75.
2.3 8, P=0.32). These results suggest that the risk of some adverse perioperative events is
greater in women than in men.
ACKNOWLEDGEMENTS
This research would not have been possible without the wisdom and guidance of my thesis
supervisor and mentor, Dr. Donald Redeheier. Drs. Geoff Anderson and Frank Silver
greatly improved this work t hrough their insightfùl comments and helpful suggestions.
Dr. John Paul Szalai provided important statistical assistance. The Librq staff at The
Toronto Hospital assisted in obtainuig key documents and references. Peter Bormann,
Mary-Claire Kavanagh, Geofney Wood, and Dr. Anne Shin provided invaluable advice,
support and technical assistance.
Dr. David Sackett, Dr. Charles Warlow and the ECST investigators and Dr. Henry
Bamett and the NASCET investigators kindly facilitated access to their trial data. The
Heart and Stroke Foundation of Canada generously provided funding for this research.
TABLE OF CONTENTS
LIST OF TABLES *.w
BACKGROUND .--... 3
2.1 EPIDEMIOLOGY OF Smou ......................................................................................................................... 3 2.1. I Definition and Causes ........................................................................................................................ 3 2.1.2 incidence and Outcornes ............................................................. ... ................................. 3 2.1.3 Risk Facro m. ........................................................................................................................................ 5 2.1.4 Carotid Srenosis .................................................................................................................................. 7
2.2 PREVEN~ON OF STROKE ............................................................................................................................. 7 2-21 Primary Prevention ............................................................................................................................. 7 2.2.2 Secondaty Prevention with Medical Therapv .................................................................................... 8 2-23 Secondary Prevention with Carotid Endarterectomy ........................................................................ 8
2.3 SEXD~FFERENCES IN VMCUL~\RDISEASE ................................................................................................ 1 1 ............................................................................................................................................ 2 . 3.1 ûverview I I
3.3.2 Coronary Artery Diseme .................................................................................................................. 11 3.3.3 Penpheral Vascular Disease ............................................................................................................ 13 3.3.4 Epidemiology of Cerebrovascular Disease ..................................................................................... I I 2.3.5 Sh-oke Prevenrion Therapy ............................................................................................................... 15
. METHODS .............-....... 19
3.1 PREAMBLE ................................................................................................................................................. 19 3.2 A D ~ ~ s T R . ~ ~ D A T ~ A S E .................................................................................................................... 20
....................................................................................................................................... 3.3 1 Background 20 .............................................................................................................................. 3.2.2 Selection Criteria 20
3.2.3 Key Variables .................................................................................................................................... 21 7 7 .............................................................................................................................................. 3.3.4 Validity --
3 -3 CLMCAL T w DATABASE ...................................................................................................................... 24 3.3.1 Background ....................................................................................................................................... 4 3.32 Selecrion Criteria for Patients in ECST and IWSCET .................................................................... 24 3.3.3 Key Variables for ECST and A'ASCET ..................................... ,, ................................................... 75 3.3.4 FaIidity of ECST and NASCET ........................................................................................................ 26 3.3.5 Main Diflerences between ECST and IWSC ET. ............ .... ....................................................... 2 6 3.3.6 Pooling ECST and NASCET Data .................................................................................................. 28
3.4 STA~STICAL METHODS ............................................................................................................................. 29
4.1 BASELINE CHARACTERISTICS .................................................................................................................... 32 4.1. 1 A dnrinisirat~e Database .................................................................................................................. 32 4 -12 Clinical Trial Database .................................................................................................................... 33
4.2 OLTCOMES .................................................................................................................................... ... ..... 33 3.2.1 Adminisrraiive Database .............................................................................................................. 33 4-22 CIinical Trial Database ................................................................................................................. 37
DISCUSSION -p.---.- 62
5.1 OUTCO~ES OF SURGERY IN WOMEN AND hax ................................................................................. 62 5.2 Lhm.~\no~s .............................................................................................................................................. 65
....................................................................................... 5.3 LONG-TERM O~TCOMES IN WOMEN AND MEN 6 9 ............................................................................................. 5.3 PREDICTORS OF SURGICAL CO~LICATIONS 69
.................................................................................................................... 5.4 BASELNE CHARACTERISTICS 70 .................................................................................................................................... 5.5 FUKJRE RESEARCH 71
........................................................................................................................... 5.6 C ~ C A L ~MPLICATIONS 73 ................................................................................................................................. 5.7 FINAL CONCLUSIONS 73
LIST OF TABLES
....... TABLE 1 : SLM~C~RY OF ~ S K FACTORS FOR PERIOPER~TIVE COMPLICATIONS FROM CAROTID SURGERY JO ................................................................................................................... T-ABLE 2: S ~ I M A R Y OF DATMASES 31
TABLE 3: CODING OF C O M O R B I D ~ IN THE ADMJM~TIVE DATABASE ............................................... 4 2 T ~ L E 4: COVARIATES FOR THE ADMMIsTRATIVE DATABASE ........................................................................... 43 TMLE 5: COVARIATES FOR THE CUNICAL TRIALS DATABASE ........................................................................... 43 T ~ L E 6: B A S E ~ E CHARACTERISTICS OF Woim N AND MEN IN THE ADbIMSTR4TWE DATAB.SE ............... 44 TABLE 7: B.~ELCNE CHAR~CTERISTICS OF WOMEN &\a MEN IN THE CLINCAL TRLAL D.AT.~.GE. ................ 1 5 TABLE 8: MORT^, MORBIDITS, DISCHARGE DESTIN-~ON AND LENGTH OF STAY [h' WOMES L0MP.UZED
TO MEN [N THE ADMINISTRA~Z DATABASE ........................................................................................... 16 TABLE 9: DISCHARGE DESTINATION OF Wohm AND WN b X l l 4 L L Y ADMlTTED FROM HOME IS THE
..................................................................................................................... A D ~ s T R ~ ~ ' E D.4Trn.4~~ 47 TABLE 10: REGRESSION MODEL FOR DEATH OR DISCI~.~RGE TO INSTI~UTIOPI'AL CARE (IF AD~üTTED FROM
H o m ) IN P.ATIENTS Di THE ADMIMSTUTIVE DATBASE ........................................................................ 48 TABLE 1 1 : REGRESSION MODEL FOR DEATH OR DISCHARGE TO LNS~ITUTION. AL C.4R.E ( R E G . ~ L E S S OF
A~MIsSIOX SOURCE) Dl PATEE~TS Ihr THE ADMNISTRAM DAT-~BASE ................................................. 48 TMLE 12: REGRESSION MODEL FOR DISCHARGE TO L V ~ O N A L CARE FOR PATIENTS ADhfITED FROS1
HOME IN THE ADMIMSTIWTIVE DATABASE .............................................................................................. 49 T.- LE 1 3: REGRESSION MODEL FOR T m n - D ~ y IN-HOSPITAL M O R T ~ T Y IN PATIE~Ts [h' THE
..................................................................................................................... ADMIMSTR4TNE DATABASE 49 TABLE 14: REGRESSION MODEL FOR EX~ENDED LENGTH OF ST-AY (> 14 DAYS) FOR P A T I E ~ S O\: THE
ADMI-NISTRATWE DATABASE ..................................................................................................................... 50 TAEILE 13: COMPARISON OF PERIOPEIWTNE M O R B ~ I T Y AND MORTALITS M WO~EN AND MEN Dl THE
CUNICAL TRIAL DATABASE ....................................................................................................................... 51 TABLE 16: REGRESSION MODEL (PARSIMOMOUS) FOR THE COMBINED EVENT OF P E R I O P E I L ~ ~ T STROKE OR
DEATH IN THE CLINCAL TRIAL DATABASE ............................................................................................... 52 T-*LE 17: COMPARISON OF M E D I C . ~ AND SCIRGICAL THERQY AT ONE YEAR ............................................. 53 T.m LE 18: COMPXRISOK OF ONE-YEIIR OUTCOMES OF WOMEN AND MEN IN THE CLNICAL TRI-AL D.-\T.~.ASE - -, ..................................................................................................................................................................... 3 J
LIST OF FIGURES
FIGURE 1 : NWER OF ENDARTERECTOAIIES ï~ WOMEX .L VD MES .................................................................... 54 FIGURE 2: P R O P O R ~ O N OF CASES ~h' P A T I E ~ S AGED 75 OR GRE.ATER ........................................................ 3 5 FIGURE 3: PROPOR~ON OF WOMEN UNDERGOING SURGERY OVER TIME ....................................................... 55
...................................................................................... FIGURE 4: PROPORTION OF WOMEN BY AGE CATEGORY 56 FIGURE 5: PLOT OF .a GE VERSUS PERCENT STENOSIS .......................................................................................... 57 FIGURE 6: PROPORTION OF CASES wnx E X ~ D E D LENGTH OF S T . ~ ......................................................... 58 FIGURE 7: P E R I O P E R A ~ Z STROKE OR DEAïïi iN WOMES AND MEN TREATED WITH END.4RTERECTOMY ......... 39 FIGURE 8, PAXEL A: IPSIL~TER LV. smou OR SURGICAL DEATH m MEN ........................................................... 60 FIGURE 8, PANEL B: IPSIUTERAL sTRoKE OR SURGICAL DEATH lir! WOhfEN ................................................. 60
. FIGURE 9 PANEL A: STROKE OR DEATH IN WOMEN &i1> hm TREATED W i ï ï i MEDICAL THERAPY .................. -61
. .................. FIGURE 9 PANEL B: STROKE OR DE-4m IN W O W hm h m TRWTED WïTH END.4RTERECTOLfY b 1
The purpose of thzs chapter zs to:
1. Provide the rationale for the study;
2. Introduce the stuàj question.
1.1 Rationale
Stroke is a common, expensive, and devastating form of neurologic injury. Carotid
endarterectomy can prevent strokes in individuais who have severe syrnptomatic carotid
stenosis. Like any major surgical procedure. however, endarterectomy can cause senous
perioperative complications. The overall esectiveness of carotid endarterectomy is a
balance between the short-term perioperative risks and long-term postoperative benefits.
It is not known whether women are at higher nsk of adverse perioperative outcornes than
men. However, the perioperative hazards may differ, since women develop carotid
stenosis at an older age when comorbid iilness cm increase surgical nsks. In addition,
women tend to have smaller blood vessels which can present technical obstacles to
successfùl surgeryl. Women also have worse outcornes following other vascular
procedures such as coronary artery bypass surgery".
1.2 Study Question
This thesis evaluates the penoperative nsks of carotid endarterectomy in women and men.
The specinc study question is: "Are perioperative complications fiorn carotid
endarterectomy more cornmon in women than in men?Determining these risks may
assist physicians in decision-making regarding the optimal treatment of carotid disease in
women, rnay lead to improvements in surgical technique, and may contribute to
knowledge in the general field of women's health.
CHAPTER 2
B A C K G R O r n
The objectives of this chqter me tu:
1. Review the epidemzology of stroke;
3 -. Summmize medical and stirgical stratepies for stroke preventzotz:
3. Present sex dfferences in the generdfield of vacuIar diseases.
3.1 Epidemiology of Stroke
2.1.1 Definition and Catcses
Stroke is dehed by the WorId Health Organization as "rapidly developing signs of focal
or global disturbance of cerebrai function, leadkg to death or lasting Ionger than twenty-
four hours, with no apparent cause other than vascular" '. This definition includes
cerebral infarction and intracerebral and subarachnoid hemorrhages. Ischemic stroke
accounts for the majority (80%) of strokes 8.9. Of these, about one third are due to lacunar
pathology (lipohyalinosis of small penetrating vessels), about twenty-five percent are due
to cardioembolism, about twenty percent are due to atherosclerotic disease and about
twenty percent are of unknown etiology Less cornmon causes of stroke inciude
vasculitis, artend dissection, and hematological disorders. This thesis focuses on stroke
due to atherosclerotic disease, particulariy extracranial carotid stenosis.
2.1.2 Incidence and Ozrtcomes
Stroke incidence ranges from about 250 per 100,000 population in those aged 55 to 65
years, to about 2,500 per 100,000 in those over the age of 85 'O. The overall one-month
case fatality rate is about 20% and the one-year case fatality rate is about 30% "-". The
five-year s u ~ v a l of aroke patients is about 50%, compared to about 90% in the general
population 'O. Case fatality rates are particularly high in older individuals and in those with
pre-existhg hypertension, diabetes, or coronary artery disease 13v1J. Case fat ality rates are
higher with hemorrhagic stroke than with ischemic stroke, and range fiom about 20% to
56% 15-17
Stroke is a leading cause of mortality in Canada, accounting for about one in every
thirteen deaths 18. Age-standardized mortality rates are about 50 per 100,000 population
for men, 54 per 100,000 population for women, and are among the lowest rates
worldwideL8. World rates for stroke rnortality range fiom 43 deaths per 100,000 women
in France to 356 deaths per 100,000 men in the Russian ~ederation". Stroke mortality
rates increase dramaticaily with age; in Canada, death rates are 3 per 100,000 in women
aged 35 to 44 versus 1,688 per 100,000 in wornen over the age of 85 18. Stroke mortality
in Canada and other industriaiized countnes has deciined by about 2% per year since the
1950's. which may be partially explained by decreased rates of smoking, decreased
prevalence of hypertension, and improvements in access to health care 13.18-21
Stroke accounts for more than 8% of hospitalization days (3 million days) in canadaz2.
The average admission for acute stroke Iasts about one month and costs about $27,500
Of those who survive, at least 25% are unable to live independently and require
placement in a long-term care facility ".12. About one in five residents in a long-term care
institution is a stroke survivor 26*27. The total costs of stroke care in Canada have been
estimated to be at least $2.5 billion per y e d 8 .
2.1.3 Risk Factors
The non-modinable nsk factors for stroke include advanced age, family history, and male
sex Afican American and Kispanic American populations also appear to be at
increased nsk of stroke compared to white populations 31. The major modifiable stroke
risk factors are hypertension, cigarette smoking, diabetes mefitus, and atriai fibrillation.
Other risk factors for stroke include hyperlipidemia, excessive alcohol consumption
hyperhomocysteinemia , obesity, a sedentary Mestyle, increased hematocrit, elevated
32 18 fibrinogen levels, and microalburninuria . In Canada, the prevalence of these risk
factors is high: 27% of the population smokes reguiarly, 2 1% are hypenensive, 44% have
hyperlipidemia, 5% have diabetes meilitus and about 2% have atrial fibrillati~n'~".
Hypertension is perhaps the most prevalent and powerful modifiable nsk factor for stroke.
The relative nsk of stroke in those with hypertension is about 2.7, and the population
attributable risk is about 50% - In the elderly. systolic hypertension is a stronger
predictor of stroke than diastolic hypertension, and even rnild elevations in blood pressure
are associated with increased stroke r i s k ~ ~ ~ ' ~ . A sustained decrease in diastolic blood
pressure of 5 mm Hg can lead to about a one-third reduction in stroke r i ~ k ~ ~ ? It is
estimated that successful treatment of dl patients with hypertension could prevent more
than 200,000 strokes annuaily
Cigarette smoking is another important risk factor for stroke. The relative risk of stroke
in smokers is at least 1.5, and the population attributable risk of stroke due to smoking is
12% 12~9.40 - That is, about one in eight strokes could potentially be prevented if everyone
were to quit smoking. Stroke risks are dose-related, with the highest risk found in those
who srnoke more than 25 cigarettes per day. With cessation of smoking, stroke risks
decrease by 50% within one year, and fa11 to the population average within five years ".
Even with active smoking cessation programs, however, quit rates are less than 6%. and
fewer than 3% of smokers become nonsrnokers each yearJL43.
Diabetes mefitus also increases the risk of stroke. The relative nsk of stroke in individuals
with diabetes is 1.8 to 3 .O, and the population attributable risk of stroke is 2% to 5% '9?
Of stroke deaths, 16% to 33% are attributable to diabetes 4s. Individuals with diabetes
may have greater morbidity and mortality secondaxy to stroke compared to the general
population30.J6. Individuals with diabetes are also likely to have other cardiovascular
disease risk factors, including hypertension, hyperlipidemia and obesityJ7 The extent to
which treatment with insulin or oral hypoglycemic agents can reduce stroke risk associated
with diabetes is unknown.
Atnal fibrillation is another common contributor to stroke, particularly in the elderly. The
relative risk of stroke with atrial fibrillation is about six, and is even higher in individuals
with concomitant mitral stenosis. The population attributable risk of stroke for atrial
fibrillation is 2% in those aged 50 to 59 years and 24% in those aged 80 to 89 years 48.
hdividuals with atrid fibrillation have an annual risk of stroke between 1% and 12%,
depending on age and other risk factors "-". In those with chronic nonvalvular atnal
fibrillation, the annual stroke risk can be decreased with warfarin therapy fiom 4.5% to
1.4% '*. Aspirin may also be effective for some subgroups with atrial fibrillation but the
evidence is much less defhitive4'.
Carotid stenosis is a narrowing of the extracranid intemd carotid artery due to
atherosclerotic disease. The prevalence of severe stenosis ranges fiom 5% to 25% in the
32-57 general population over the age of 50 . Both the prevalence and the severity of carotid
stenosis increase with age, hypenension, smoking and hyperlipidemia 53-55.574 1 . The risk of
stroke from carotid stenosis increases with the severity of stenosis. and is greater in those
with recent symptoms of cerebral ischemia than in those who are asymptomatic6"'. In
syrnptornatic patients, annual stroke risks are Iess than 1% in those with mild stenosis.
about 4% in those with moderate stenosis, and about 13% in those with severe stenosis
6264.65 - In asymptomatic patients. annual stroke risks are about 1% in those with any
degree of stenosis, and about 2% in those with severe stenosis 63.66.
2.2 Prevention of Stroke
2.2. I P rzmary Prevention
Primary stroke prevention requires rïsk factor modification. This typically focuses on
control of hypertension, diabetes and hyperlipidemia, smoking cessation, and
anticoagulation in the setting of atrial fibrillation 39-48. Acetylsalicyiic acid (ASA) does not
appear to be effective for prirnary stroke prevention, even in those with documented
67-69 carotid stenosis, although the studies could not exclude a smd benefit . Carotid
endarterectomy for primary prevention in patients with asymptomatic severe carotid
stenosis has been tested in four randomized trials, of which only one showed a decrease in
the risk of stroke and death 63-70-72 . Moreover, in this study, the benefit of surgery
appeared only over a five-year penod and was associated with substantial immediate
perioperative rIsk of stroke or death.
2.2.2 Secondry Prevention with Medical ïherapy
Several randomized trials have established the effectiveness of antiplatelet agents for the
secondary prevention of stroke 25.73-87 Overall, ASA at a daily dose of 900 to 1300 mg
reduces the risk of recurrent stroke by 23%". One trial found that a dose of 325 mg was
not significantly different fiom 1300 mg daily compared to placebo87. Other trials have
demonstrated equivalence of low dose (30 to 80 mg) ASA with 315 mg daily, but these
did not include a high-dose arm80*86. Controversy persists regarding the optimal dose of
AS A 80.81.86.87.89.90 . Ticlopidine hydrochioride has also been studied in randomized
controlled trials. and has a relative risk reduction of 30% over placebo and 2 1% over ASA
83.85
2.2.3 S e c o n h y Preventzon with Curotid Endarterectomy
Carotid endarterectomy is a surgical procedure to remove atherosclerotic plaque corn the
intemal carotid artery. It was first performed in 1954. The procedure is usuaiiy
performed under generd anesthesia, but c m also be done using regional blocks. EEG or
monitoring of evoked potentials is often empioyed intraoperativeb to evaluate the
adequacy of cerebral blood flow. Some surgeons routinely place a shunt to rninimize
cerebral ischemia dunng cross clamping, while others only perform shunting if
intraoperative monitoring detects abnormalities ''. Patch grafts or vein g r d s may be used
92-94 for arteriotomy closure . A typical endarterectomy Iasts about ~ n e t y minutes. costs
about $700 in surgical fees, and engenden about $1 1,000 in total health care costs 95.
In Ontario, utilization of carotid endarterectomy for people aged 45 and over in 1 98 1 /82
amounted to a total of 1178 procedures %. The rate of endarterectomy declined in
subsequent years to a low in 1989/90 of 606 procedures, presumably related to
controversy surrounding the effectiveness of the procedure. Following the publication of
triais demonstrating the benefit of endarterectomy in individuals with symptomatic severe
carotid stenosis, utilization of endarterectomy increased to L202 procedures in 199 1/91
6264 - Similar trends have been seen in the United States and other countnesg7. One review
of endarterectornies done on Medicare beneficianes found that the surgery was
appropnate according to current guidelines in 96% of cases. and that about half of
procedures were performed on asymptomatic patients98. In the Toronto area, about 20%
of procedures are performed on patients with asyrnptomatic disease (Jack Tu. persona1
communication).
Endarterectomy has been shown to be effective in two iandmark trials: the North
Amencan Symptomatic Carotid Endarterectomy Trial (NASCET) and the European
Carotid Surgery Tnal (ECST) 626J. Both trials randomized individuals with severe carotid
stenosis (70% to 99%) and ipsilateral symptoms to receive or not receive carotid
endarterectomy. NASCET found that the nsk of stroke or death was substantiaily lowered
by surgicd therapy compared to medicai therapy (9% versus 26%). ECST found that the
nsk of major stroke or death was aiso lower with surgical therapy (1 2% versus 22%).
Since the publication of both triais in 199 1, endarterectomy has become the standard of
care for symptomatic patients with severe carotid stenosis. Recent data fkom NASCET
suggests that endarterectomy is also effective in individuds with greater than 50%
stenosisg9-
The main drawback to endarterectomy is the risk of perioperative complications. The
most serious complications are death, stroke, myocardial infarction nerve injury. wound
hematorna, and infection. For patients with severe stenosis, the risks of perioperative
stroke or death were 6% and 4% in NASCET and ECST. respectively. A review of other
studies of endarterectomy for symptomatic carotid stenosis also reported rates of
penoperative stroke or death ranging from 5 to 9%, although rates as high as 20% have
been reported 1.100-107 - The American Heart Association now recomrnends that
endarterectomy only be perfomed by surgeons with surgical complication rates of less
than 6%'".
Many studies have explored patient characteristics that may be predictive of penoperative
complications (Table 1). Risk factors identified in some studies include older age,
hypertension, diabetes, coronary artery disease, contralateral occlusion, ipsilateral carotid
ulceration, symptomatic cerebrovascular disease, previous hernispheric stroke, infarction
on computed tomography, and failure to use aspinn perioperatively 19L99.105-110 . Other
potential risk factors include the use of general rather than local anesthesia, pnmary
arterial closure rather than patch closure, surgery on the lefi carotid artery, and surgery at
a low-volume institution 91.99.1 11-113 - Of note, however, none of these factors have been
consistently associated with increased surgical risks, and most studies have found that
patient factors explain only a s m d component of variation in surgical risks 1.108.1 10.1 14-1 18
Penoperative strokes are usually ipsilateraI, and appear to be caused by embolization or
occlusion'0s. About haif of perioperative deaths are stroke-relatedHg.
2.3 Sex Dserences in Vascular Disease
2.3.1 Ovewiew
Men and women with coronary and penpheral vascular disease have dserent baseline
charactenstics, different rates of diagnostic testing and surgical intervention, and different
surgical outcomes. Since atherosclerotic disease is a synemic disorder, these observed
differences may have important implications for women with cerebrovascular disease who
undergo carotid surgery. The following section reviews studies on sex differences in the
management of coronary artery disease, peripherat vascular disease and cerebrovascular
disease.
2.3.2 Coronary Artery Disease
Women with symptoms of coronary artery disease are about half as likely as men to be
referred for noninvasive diagnostic testing, have symptoms for about five months longer
than men pnor to testing, experience more atypical pain, and are twice as likely to be
prescnbed a n x i ~ l ~ t i c s ' ~ ~ . Women with positive noninvasive tests are about half as likely as
men to be referred for angiography, even foilowing an acute myocardial infarction or
unstable angina 27.320-123 . Some c l a h that this reflects excessively high use of angiography
in men rather than inappropriately low use in women 12-t.12~ - Once patients undergo
angiography, men and women appear equally Kkdy to be referred for revascularization,
although patterns of referral are dif5erent 121.126 . Women are more iikeiy to require
emergency surgery 23-121.127.128 Among iower risk patients where surgery offers little
s u ~ v a i benefit, men are referred more often; among higher nsk patients (with lefi main
stenosis, mitral insufficiency, and severe pain) where surgery offers the greatest expected
suMval benefit, women are referred more often '". At the t h e of revascularization.
women are several years older than men, are-more IikeIy to have unstable angina,
congestive heart failure, hypertension and diabetes. and are less likely to smoke cigarettes
24.5.121-128 - Together, these observations lead some to speculate that women are relatively
neglected and are referred for surgery at a later stage of disease 12!
Women and men who survive coronary revascularization appear to have sirnilar long-term
outcornes. However, in most case senes and database analyses, the surgical mortality of
women undergoing coronary artery bypass grafiing is approximately twice that in men. 2-
6.130 . In those studies that adjust for other prognostic factors, some but not al1 of this
increased risk is attributable to the relatively older age and greater comorbidity in wornen
4.126.13 1 - Smaller body size with smaller coronary vessels has also been found to contribute
to the greater hazards for women '. The reasons why higher surgical mortaiity rates
persist in women, even afier correction for age. comorbidity and size, remain a topic of
3.132 ongoing research .
2.3.3 Penpherd Vc~scular Dzsease
Little is known about dserences in diagnostic testing and therapy in men and women with
peripherai vascular disease. One study found that women referred for noninvasive testing
had a worse ankle to brachial blood pressure gradient than rnenl3'. m e r noninvasive
testing, no significant sex dflerences were found in the aggregate rates of
revascularization (29% and 21% in men and women, respectively), but there was a trend
for men to be referred for surgery more often in the least ischemic and presumably more
discretionary group (20% versus 12%). Among patients who did not need limb salvage.
men were again more likely to be referred for surgery (19% versus 9%) '? These hdings
parallel those found with coronary revascularization, where wornen do not receive
therapeutic interventions until they have reached a more advanced stage of disease.
At the time of peripheral revascularizatioq women are about three years older than men,
are more likely to have hypertension, less likely to smoke cigarettes. and equally likely to
have diabetes, coronary artery disease and other comorbid conditions 133-136 . It is not
known whether men and wornen have different outcomes following peripheral
revascularization. Although some trials have docurnented a trend towards higher surgical
mortaiity in women, as well as worse three-year survival and lower graft patency, other
triais have found surgical risks and outcomes to be identical in men and women 134-137
2.3.4 Epzdemiology of Cerebrovmsculur Diseose
Women have a lower iifetime risk of stroke than men (1 8% versus 25%) Is. However.
because women are over-represented in the older age groups and stroke mortaiity is
higher with older age, women have a greater lifetime risk of dying from stroke ( 1 1 %
versus 7%). In Canada in 1 995, for example, stro ke accounted for 895 1 deaths in women
and 6586 deaths in men 18. The Framingham study found higher stroke recurrence rates in
men, however, this has not been c o h e d in subsequent cohort studies 10.138.139
Stroke severity is the same in both sexes after adjusting for age. and men and women
ï3.138 appear to suffer equal cognitive and fùnctional deficits following stroke . Among
stroke s u ~ v o r s , however, women are less likely than men to make a complete recovery
(37% of women versus 50% of men), and are more likely to be dependent on others for
self-care activities (27% of wornen versus 16% of men) la. Hospitalization for acute
stroke is longer and therefore more costly for women than for men ($32.000 versus
$23,000 per admission) ". At tirne of discharge from hospital, women may be more likely
to be transfemed to long-term care facilities. while men may be more likely to go home or
to rehabilitation facilities Women with stroke are less likely than men to have family or
social supports (39% versus 82%) ".
On average, women are several years older than men at the time of first stroke 10.23.139
The prevalence of major stroke risk factors, including hypertension, diabetes,
hyperlipidemia, and cigarette smoking is similar in men and women 18. However, f i e r age
55, the prevaience of hypertension is more cornmon in women than in men14'. In addition,
smoking rates are declining more slowly in women than in men, and it is estimated that
smoking rates 4 1 be higher in women than men by the year 2000 46. Men are more likely
to have atrial fibriilation '*. However, because women are over-represented in the older
age groups, and atrial fibrillation is more common with increasing age, the absolute
number of men and women with atrid fibrillation is approximately equal Some studies
have found no difference in the prevalence of carotid stenosis in men and women. but
others report a greater burden of disease in men s ~ - s J . s ~ . ~ ~ . ~ o . ~ J c 16 Women develop stenotic
plaques several years later than men 53.54.59.60 . Women with carotid stenosis may have
Iower stroke rates than men: a subgroup andysis of NASCET patients with moderate
stenosis (50% to 69%) found that the five year stroke risk was 15% in women compared
to 25% in menug.
2.3.5 Stroke Prevention Therapy
Antiplatelet Therapy
Subgroup analyses of some trials of ASA for stroke prevention have failed to show a
benefit in women, Ieading to the hypothesis that testosterone modulates ASA'S beneficial
effects on platelet aggregation 25.75.87.144145 . However, these trials had insufficient power
ro exchde a benefit in women, and ASA has been shown to be effective in wornen in other
tfialS "-78.79 . Thus, it is likely that ASA is effective therapy for stroke prevention in both
women and men. Trials of ticlopidine hydrochioride in stroke prevention have
demonstrated simiiar benefits in both sexes 83?
Surgical Therapy
Data fiom several studies indicate that carotid endarterectomy is perfonned more ofien in
men than in women 9297.146 - Some of this irnbalance rnay be explained by sex dinerences in
the underlying prevaleace of carotid stenosis. However, it is ais0 possible that
endarterectomy is relatively undemtilized in women compared to men. Physicians may
not recommend endarterectomy for women because of a perception that women benefit
less fiom surgery, either because of higher surgical nsks or because of lower baseline
stroke nsks. Women may refuse endarterectomy because of an underestimation of stroke
risk or because of insufficient social supports to contemplate surgery and
con~alescence'~~. Studies of other surgical procedures, such as coronary artery bypass
grafking, have found that lower procedure rates in women are related to lower referral
rates for noninvasive t e ~ t i n ~ l ~ l . ' ~ ~ . In contrast, one study of procedures for
cerebrovascular disease found that women were oniy 9% less WceIy than men to undergo
cerebral angiography, but were 60% less likely undergo carotid endarterectomyg7.
The relative nsks of carotid endarterectomy in men and women are not well established.
Several surgicai series have failed to demonstrate a difference in the perioperative nsks of
women and men undergoing carotid surgery 9ZlIS.117 . In addition, an analysis of
administrative data fiom North Carolina found no difference in the risk of stroke or death
in wornen and men although the authors did not adjun for age or c~morbidit~"'~.
However, other data suggest that women face higher surgical complication rates. One
large surgical series found that women were at higher risk of perioperative stroke or death
compared to men, although there was no adjustment for comorbid conditions (odds ratio
1.9, 95% confidence interval 1.0 to 3.7, ~ = 0 . 0 5 ) ' ~ ' . In a randomized study of patients
with asymptomatic stenosis, the rate of penoperative stroke or death was 4% in women
and 2% in men, although this dserence was not statisticdy significant 63. Preliminary
results from an ongohg randomized trial of aspirin and carotid endarterectomy also
showed a trend towards an increased risk of perioperative stroke or death in women
compared to men (6% vs. 4%, ~=0.06)'~~. A review of endarterectomies performed in
Medicare beneficiaries in one US. state found a trend towards higher surgical
complication rates in women, even f i e r adjustment for age, race. Charlson comorbidity
score, and hospital surgical volume (odds ratio 1.67, 95% confidence interval, 0.9 to
2.5)'! Finally, a meta-analysis of six published studies (one randomized trial. five surgical
senes) as weU as unpublished data from ECST found that the odds of stroke or death were
increased in women (odds ratio 1.44: 95% confidence interval, 1.14 to 1.83; p<0.005) '.
However, there was no adjustment for other prognostic factors, and data from other
randomized t d s were not included in the analysis. in addition, oniy six of the thirty-six
articles reviewed by the authors included information on sex as a prognostic factor.
Therefore, it is possible that the observed increased risk in women was the result of
publication bias. with studies only reporting results on the basis of sex if an interesting
trend was observed.
m e r surgery, some data suggest that women have higher rates of carotid restenosis than
men (24% versus 8%) "94. Restenosis rates in women appear to be reduced with the use
of patch grafts for artenotomy ~ l o s u r e ~ ~ * . Since patch grafts increase the lumenal
diameter of the carotid artery, some hypothesize that smailer arteries in women may
68.69 uicrease the risks of restenosis . However- one study found no relationship between the
intemal carotid artery diarneter and the risk of recurrent ~enos is"~ . Moreover, most
148.149 episodes of carotid restenosis are asyrnptomatic and do not require reoperation -
In summary, the existing literature does not provide a definitive answer to the question of
whether or not women undergoing carotid endarterectomy face higher surgical rïsks than
men. To our knowledge, few snidies have compared the risks of perioperative stroke or
death in men and women with adjustment for comorbidity, and no study has used
population-based administrative data or individual patient data fiom more than one
rando mized triai.
The objectives of this chupter me to:
1. Provide an overview of the stuc@ rnethodology;
2. Describe uZZ databases, with attention to selection criteria und vulidiv;
3. Derail Ihe statistrkd methods zrsed for &tu malysis-
3.1 Preamble
This project applied two independent strategies to compare the risks of carotid surgery in
men and women. Fust, administrative data on patients who undenvent carotid
endarierectomy in Ontario between 1982 and 1994 were exa.mined to compare the rates of
institutionalization (discharge to chronic care, nursing home. or rehabilitation facility). in-
hospital mortaiity, and length of stay in men and women. This aim of this retrospective
cross-sectional analysis was to determine the rkks of carotid surgery under typical
conditions. Second. data ftom two chical trials of endarterectomy (NASCET and ECST)
were exarnined to compare the risks of surgical stroke and death in women and men. The
aim of this analysis was to determine the risks of carotid surgery under more controlled
circumstances. Together, these two analyses provided a rigorous method for evaluating
the relative nsks of carotid surgery in women compared to men (Table 2). The
prespecified study hypothesis was that risk of penoperative complications would be
greater in women than in men.
3 -2 Administrative Database
3- 2. I Background
The database ofthe Canadian Institute for Health Information ( C m gathers
administrative information obtained from hospital discharge abstracts. By law in Ontario.
all separations (discharges, transfers, deaths) fiom acute care hospitals are included in the
database. Trained healt h records tec hnicians at each hospital site abstract data from
hospitalization records, including the patient's date of birth, dates of hospital admission
and discharge, information on procedures performed, consultations, and primary and
secondq diagnoses. Diagnoses and procedures are coded using the International
Classification of Diseases, 9U revision (ICD-9) or the ICD-9 Clinical Modification (CM)
and the Canadian Classification of Diagnostic. Therapeutic and Surgical Procedures (CCP)
bookS 150.151 - C W retums any incomplete abstracts to the hospitals for editing. ensuring
that data are relatively complete.
In this study we identified alf endarterectomies performed on patients in acute care
hospitals in Ontario between 1982 and 1994. To do so, we searched the CIHI database
using the CCP code 50.12 C'endarterectomy on vesse1 of neck"). Ail procedures were
included in the database, including repeat procedures on the same patient and
endarterectornies performed in conjunction with other procedures.
3.2.3 Key Variables
For each individual, baseline information on sex, age, date of procedure. hospital.
admission source, and comorbid conditions was abstracted. The number of procedures
performed at each hospital was tabulated, and institutions were identified as iow-volume if
they performed an average of fewer than twenty-five endarterectomies annuaiiy. This
definition of low-volume was selected based on the NASCET requirement that surgery be
performed in institutions performing a minimum of fifty endarterectomies over two years.
Comorbid conditions were identified by the secondary diagnosis codes in the C H
database. Based on these comorbid conditions, a modined Charlson comorbidity index
score was calculated for each individual 152. The modified Charlson-Deyo index was
created by matching the seventeen medical conditions in the original Charlson index with
the corresponding ICD-9 codes in the C W database, and obtaining a weighted sumrnary
score lS' (Table 3). A score of zero indicates that no comorbid illness is present. and
higher scores indicate a greater burden of comorbidity. This modified index has been
developed and used for nsk adjustment with administrative data 152.IS-i-156
The primary outcome measure was the combined endpoint of in-hospital death or
discharge to institutional care. Specifk perioperative complications (coded as type 2
diagnoses) were not used as the pnmary outcome measure because the coding of these
conditions is unreiiable (see below). Death was defined as death within 30 days of
admission, consistent with the definition of penoperative death in the dinical trials. Only
those deaths that occurred durùig the index hospitalization were captured in the database.
Institutional care included nursïng homes, chronic care institutions, rehabilitation facilities
and other institutions. In order to rninunize the risk of detecting minor differences in
patterns of care, a discharge with home care (a suitable option for most patients with
rninor postoperative issues or insufficient social supports) was not considered institutional
care, but was counted as a separate endpoint. Shce some patients were initially admitted
fiom institutions, a discharge to institutional care was counted as a primary endpoint only
ifthe patient had origindy been admitted from home. In-hospital mortality, specific
discharge destinations and length of stay were secondary outcornes. Data on selected in-
hospital complications, including stroke, myocardiai infarction, and local surgical
complications were also available. A complication that was coded as both the rnost
responsible diagnosis and a type 2 diagnosis (complication) was designated as a
"complication as the most responsible diagnosis".
An administrative database provides an enormous sarnple size and the oppominity for
population-based sampling. Individuals do not need to be contacted directly, which
etiminates participation problems and recall bias '". However. the use of administrative
databases for research purposes has important limitations. First, detailed clinical
information may be lacking, including the factors of greatest interest such as clinical risk
factors. functional status, and quality of life. Second. available data may be coded
incompletely or inaccurately, particularly comorbidity, complications, and chronic
conditions 15""s161. Finally, it is often dificult to distinguish whether a coded diagnosis is
a comorbid condition present before admission, or a complication occurring dunng
hospitabation 16'.
The vaiidity of the C W database has been assessed in seven reabstraction studies "'.
Overdl, less than three percent of the records fiom Ontario are rnissing ciamographic data
15 1 Agreement with the hospital record is 99.5% for admission date, 99.1% for discharge
date, 99.2% for sex, 98.5% for birth date, 97.8% for admission source, 97.3% for
discharge destination, 88% to 96% for principal procedure code, and 100% for death 150.
Thus, the database is reasonably reliable for baseline demographics and simple hospital
data. However, agreement for diagnoses is not as good, with only 81% agreement for
"most responsible diagnosis" and false negative rates in excess of 60% for coding of
specific comorbid conditions and complications 150.15 1.163
Because of these coding deficiencies, the C W database has limited validity for the direct
analysis of perioperative complications. However, it does include complete and valid data
for the analysis of the pnmary endpoint of in-hospitai death or discharge to institutional
care, as well as the endpoint of length of stay. Other studies using administrative databases
have found that both extended length of stay and discharge to institutional care can be
indicative of in-hospital compIications 161.164 . Hence, in this study we use discharge to an
institution as a reflection of a major surgical complication.
3 -3 CIinical Trial Database
3.3.1 Background
ECST and NASCET were multicenter trials of carotid endarterectomy for patients with
carotid stenosis and ipsilaterai ischemic ~ y r n ~ t o r n s ~ ~ " . Individuals were randomked to
receive or not receive ipsilateral carotid endarterectorny. Randomization was stratified
based on the degree of carotid stenosis, resulting in three strata in ECST (mild. moderate.
and severe stenosis) and two strata in NASCET (moderate and severe stenosis).
Randomization in ECST was asymrnetric, with 60% allocated to surgical treatment and
40% docated to nonsurgical treatment. AU patients in both trials received medical
therapy, including aspirin, treatment of hypertension and advice to stop smoking. For
patients with severe stenosis, the mean duration of follow-up was 2.7 years in ECST and
1.5 years in NAS CET.
Both studies demonstrated an overall benefit fiorn carotid endarterectomy for patients
with severe stenosis. In ECST. the risk of death or disabling stroke at three years was
11% with medical therapy and 6% with surgery. The risk of major nondisabling stroke or
death was 22% with medical therapy and 12% with surgery4'. In NASCET, the risk of
ipsilaterd major or fatal stroke at two years was 13% with medical therapy and 2% with
surgery. The risk of any ipsilateral stroke o r death was 26% with medical therapy and 9%
with surge$*.
3.3.2 Selection Criferia for Patients in ECST ond NASCET
Both ECST and NASCET enrolled patients with carotid stenosis and recent (within six
months for ECST and four months for NASCET) ipsilateral caratid territory symptoms.
Both triais excluded patients with carotid occlusion, severe distal cerebrovascular disease.
presumed cardiac emboli, pnor ipsilateral endarterectomy, prior major stroke,
uncontrolled diabetes, or uncontrolled hypertension. In addition, NASCET excluded
patients older than 80 years, those with an estirnated Life expectancy of less than five years
and those wit h recent rnyocardial infarction, contralateral endart erectomy, or major
surgery . ECST excluded patients with rend failure, chronic obstructive pulmonary disease.
concomitant anticoaguiant use, and those who were deerned umeliable.
3.3.3 Key Vananables for ECST and NASCET
For this study, data on ail patients with severe stenosis was obtained directly from the
ECST and NASCET investigators. Baseline clinical and angiographie variables included
age, sex, degree of stenosis, the presence of contralateral stenosis, the type of qualfiing
event, and comorbid conditions. Surgical variables included the type of anesthesia. and
the use of EEG monitoring, shunting, and patching dunng surgery.
For the analysis, the principal outcorne measure was perioperative stroke or death.
Perioperative stroke was defined as any stroke. regardless of location, which occurred
within one month of surgery. Because of coding differences in the two studies, this
included strokes lasting more than seven days in the ECST database, and strokes lasting
more than one day in the NASCET database. Perioperative death was defined as any
death, regardless of cause, that occurred within one month of surgery. Secondary outcome
measures were perioperative death alone, perioperative stroke alone, major perioperative
stroke or death, perioperative myocardial infarction, local surgical complications. and
ipsilaterai stroke or death at one year.
3.3.4 Vuiidiiy of ECST and NASCET
Both ECST and NASCET were weii-designed randomized t i a l s with excellent intemal
validity. Moreover, quality assurance and data entry were superb. A blinded audit
cornmittee assessed outcomes and patient foilow-up was nearly complete. Valid data on
penoperative stroke and death were available for al1 patients who underwent surgery.
since these were p r i r n q outcomes in the original studies. There was very little missing
data, atthough data on selected baseline characteristics were lacking in six patients and
data on the use of intraoperative EEG monitoring were lacking for 14 1 patients. As in
most randomized controlled trials, however, the men and women who agreed to
participate may not be representative of the typical patient with carotid srenosis and the
generatizability of results may be Iimited to patients who are similar to the study
population.
3.3.5 Mazn Drf/ereitces betweerz ECST and NASCET
Some dserences between ECST and NASCET ment comment. ECST was performed in
more than eighty European medical centres whereas NASCET was performed in fifty
North Amencan medical centres. ECST had no specifîc centre eligibility criteria whereas
a centre was eligibie for inclusion in NASCET only if it had a demonstrated surgicd
complication rate of less than 6% for ar least fifty consecutive endarterectomies perfomed
within the previous two years. The q u a m g symptoms had to have occurred within the
preceding six months in ECST and within the previous four months in NASCET. Patients
over the age of eighîy were included in ECST but excluded fkom NASCET. Patient
enrolrnent in ECST was based on the "uncertainty principle". whereby patients were only
offered the oppominity to participate if the local neurologist and surgeon were
"substantially uncertain" whether or not to recommend endarterectomy. Otherwise. the
patients in these two trials were similar.
Another major dEerence is that the two trials used different methods to determine the
degree of stenosis on cerebrd angiography. In ECST, percent stenosis was calculated by
dividing the luminal diameter at the point of maximal stenosis by the estimated nomal
lumen diarneter at this site '. In NASCET, percent stenosis was caiculated by dividing the
luminal diameter at the point of maximal stenosis by the diarneter of the disease-free distal
lumen. Because of this methodological dserence, neariy 50% of those in ECST ciassified
with severe (70% to 99%) stenosis would be reclassified as having moderate (30% to
69%) stenosis using NASCET riten na'^^.
The clinical, angiographic. and surgical variables available in the ECST and NASCET
databases were similar aside from minor coding differences. Both databases documented
death, cause of death, stroke, and stroke severity. In ECST, strokes lasting more than
seven days were considered major. and those resulting in persistent significant disability
(modified Rankin grades 3 ,4 or 5) at six months were defined as disabling. In NASCET,
al1 events lasting more than 24 hours were defined as strokes, and a stroke producing
fùnctiond deficits beyond ninety days was considered major. Otherwise, the definitions
used for identdjing patient outcomes were similar.
3.3.6 Pooling ECST and NASCET Data
In this study, key variables fiom ECST and NASCET were combined to form a singie
Iarge database, hereafter called the clinical trial database (Table 1) . The baseline variables
in this database included age, sex, degree of stenosis, contralateral occlusion, type of
qualifying event, comorbid conditions, and technical details surrounding the surgery. The
key outcome variable was the combined endpoint of perioperative stroke or death.
Because of coding dierences between the two trials, the outcome of stroke in the pooied
database consisted of the outcomes of "major stroke" (lasting more than seven days) fiom
ECST and "any stroke" (lasting more than one day) from NASCET. The outcome of
major stroke in the pooled database consisted of the outcomes of "disabling stroke" from
the ECST database and "major stroke" fiom the NASCET database.
3 -4 Statistical Methods
The distributions of baseline chnical characteristics were compared in men and women by
using a t-test for continuous variables and a chi-square test for categoncal variables. For
the administrative database, the main analysis compared the endpoint of in-hospital death
or discharge to institutional care in women and men, with adjusmient for age and other
baseline characteristics by means of logistic regression 16'. For the clinical trial database,
the main analysis compared perioperative death or stroke in women and men, again with
adjustment for age and other baseline characteristics through logistic regression.
A regression model was developed for the administrative database with al1 risk factors of
known or presumed biological significance included as independent variables in the initial
model (Table 4). Age and age-squared were both initialiy analyzed, however, prelirninary
analyses suggested that the risk of adverse events was relatively constant before the age of
seventy, and that risks increased substantially after this age. Therefore, the fuial model
coded age as a dichotomous variable (age greater or less than seventy years) for
simplicity. Interaction terms for sex and each predictor variable were examined, but no
statistically significant interaction effects were found and these were not included in the
final model. All variables were entered into the model simultaneously without the use of
stepwise or conditional procedures. Secondary analyses also compared endpoints of
survival, discharge destination, the logafithrn of length of stay, and extended length of stay
(defhed as more than fourteen days) in women and men, with adjustment for age and
other clinical characteristics by means of regression techniques.
Power calculations were performed using death or discharge to institutional care as the
primary outcome event. Assuming a sample size of 12,000 (one third wcmen), two-tailed
p values, alpha=0.05, beta=0.80, and an event rate of 3% in men (baseci on the risk of
major stroke or death in the ciinïcal triais), there was sufficient power to detect a relative
risk of greater than 1.2 or less than 0.8 in women compared to men.
A regression model was developed for the clinical trial database with all risk factors of
known or presumed biological signincance included as independent variables in the initial
model (Table 5). An interaction term for source of data (ECST or NASCET) and sex was
inciuded; no other interaction terms were added because of the risk of ovefitting. The
initial model included a large number of independent variables for the prediction of a
167.168 relatively rare event, which can result in unstable estirnates . Therefore. regression
modeliing was also performed using a parsimonious mode1 which included oniy those
variables which were significant at the p=0.10 levei in the univariate analyses.
The two clinical trial databases were initially analyzed as a pooled database, and the tria1
source was included as a covariate. Secondary analyses compared results in the two
individual trials. Further secondary analyses were conducted using the entire clinical trial
database, including patients assigned to medical therapy. In this group. the analysis
compared men and women on time to event using Kaplan-Meier s u ~ v a l curves and the
Cox proportionai hazards model. Treatment failure was defined as ipsilateral stroke or
death, and was adjusted for age, stenosis, contralateral occlusion, treatment assignment
and cornorbidity. Results were aiso analyzed in terms of the proportion in each group
who reached other endpoints during the follow-up tirne.
Power caiculations were performed using penoperative stroke or death as the primary
outcome event. Assuming a sample sire of 900 (30% women), a 6% event rate in men.
two-tailed p values, aIpha=0.05, beta=0.8O1 there was sutficient power to detect a relative
nsk of stroke or death ofgreater than 1.54 or less than 0.64 in women compared to men.
Statistical analyses were performed using SPSS software. Aithough the study hypothesis
could support the use of one-sided tests, by convention ali P-values were two-tailed. and
were considered significant at the 0.05 level. Cornparisons are presented in terms of odds
ratios for events in women compared to men, dong with 95 percent confidence intervals.
For the long-tem outcomes. results are presented in terms of Kaplan-Meyer suMval
curves. In order to presewe patient confidentiality. a unique patient identification number
identified patients in both databases, without reference to name o r other identifiing data.
Neither patients nor physicians were contacted directly. The snidy received ethics
approval tiom the University of Toronto.
CHAPTER 4
RESULTS
The objectives of this chopler are to:
1. Presenr the baseline characteristics of patients in the admirzistratïve abtczbcrre ajzd
in the pooied clinical tria! dntabase;
2. Present cornparisons of death or discharge to i~~~titz~tio~zui c m and other
endpoints for men and women in the administrative database;
3. Present cornparisons of the rish of perioperative stroke or death and other
endpoints for men and women irz the chical nial database;
4. Present results of comparisons of one-year outcornes in men and wornetr i t ~ the
clinical triai database.
4. I Baseline Characteristics
4.1.1 Administrative Da~abase
The study sarnple consisted of 12,949 patients who undement carotid endarterectomy in
Ontario between 1982 and 1994. Overall, 35% were women, and 65% were men (Table
6) . Surprisingly, men and women had the same average age (66 years). Men and women
had similar baseline characteristics, except that a higher proportion of men had c o r o n q
artery disease, a history of COPD, and a Charlson comorbidity score exceeding one (Table
6). Overall rates of comorbidity were remarkably low, with only 5% having two or more
problems. Alrnost al1 patients were admiîted diredly from home, and most patients had
surgery at a high-volume institution. Women were no more Iikely than men to be admitted
f?om institutionai care or to have surgery at a low-volume institution.
AIthough the proportion of elderly patients undergoing surgery increased after 1 99 1, the
proportion of women undergoing endarterectomy was constant over the time period
studied (Figures 1,2,3). In addition, the proportion of women undergoing surgery was
the sarne in every age category, despite increases in the proportion of women in the older
age categories in the generd population (Figure 4).
4 1 . 2 Clinjeal Trial Dafabase
The study sample consisted of 1646 patients with severe carotid stenosis, of which 30%
were women and 70% were men (Table 7). A total of 923 received surgical therapy. Men
were more likely than women to have a history of myocardial infarction or peripheral
vascular disease, and were less likely to have hypertension. Otherwise. there were no
significant differences between the baseline or surgical characteristics of men and women
in the clinicai trial database. There was no difference in the degree of carotid stenosis in
men and women, regardless of age, and there was no significant correlation between age
and percent stenosis (Figure 5). Again, surpnsingly. the average age of men and women
was identical (63 years).
4.2 Outcornes
4 2 . 1 Aahznistrative Database
Death or Lnstitutionalization (Combined Outcorne)
Five percent of patients died in hospital within thirty days or were adrnitted from home but
discharged to institutional care (chronic care, rehabiiitation facilities, nursing homes and
other institutions; not home care). In the univariate analysis, women were slightly more
likely than men to die or be discharged to institutional care (odds ratio 1.18, 95%
confidence interval 0.99 to 1.40, p=0.07) (Table 8). After adjustment for age and other
risk factors, women were at somewhat higher risk of in-hospital death or
institutionalization than men (odds ratio 1.19, 95% confidence interval 1.00 to 1.4 1.
p=0.05) (Table 8). In the logistic regression analysis, age over seventy. higher Charlson-
Deyo scores, year of surgery and surgery at a low-volume institution were significant
predictors of death or institutionalization (Table 10).
In the analysis of al1 patients in the administrative database. regardless of admission
source, six percent of patients died or were discharged to institutional care (Table 8). In
the univariate analysig women were at higher nsk of death or institutionalization than men
(odds ratio 1.23, 95 percent confidence interval 1 .O6 to 1.44, P=0.007). After adjustment
for age and comorbidity, the odds ratio for this outcome in women compared to men was
1-25 (95 percent confidence interval, 1 .O7 to 1-46, p=0.005) (Table 8). Other predictors
of this outcome were age over seventy, higher Charlson-Deyo scores, year of surgery and
surgery at a low-volume institution (Table 1 1).
Discharge to Institutional Care
Of patients who were admitted from home, 3% were discharged to institutional care
(Table 8). Women admitted fiom home were more likely than men to be discharged to
institutional care, with an odds ratio of 1.38 (95% coddence interval 1.12 to 1.70.
p=0.003) (Table 8). M e r adjustment for age and other risk factors. the odds of discharge
to institutional care for women compared to men was 1.39 (95% confidence inrerval 1.13
to 1.72, p=0.002) (Table 8). Other baseline factors predictive of discharge to institutional
care were age over seventy, higher Charlson-Deyo scores, year of surgery and surgery at a
low-volume institution (Table 12).
When specific discharge destinations were analyzed, women were more likely than men to
be discharged to rehabilitation facihies (odds ratio 1.60, 95% confidence interval 1.15 to
2.24, P=0.006) (Table 9). M e r adjustment for other risk factors, female sex remained a
si@cant predictor of discharge to a rehabilitation hospital (odds ratio 1.62, 95%
confidence interval 1.16 to 2.27, P=0.005) (Table 9). Women were slightly more likely
than men to be discharged to chronîc care facilities. but this was not statistically significant
(unadjusted odds ratio 1.40, 95% confidence interval 0.83 to 2.39, P=0.2 1; adjusted odds
ratio 1.44, 95% confidence interva1 0.84 to 2.45, P=O. 18) (Table 9). Women and men
were equally likely to be discharged to acute care hospitals.
Discharge With Home Care
Women initially admitted from home were significantly more likely than men to b e
discharged with home care (odds ratio 1.85, 95% confidence interval 1.47 to 2.32,
P<0.0001) (Table 9). M e r adjustment for age and other risk factors, the odds of
discharge with home care for women compared to men was 1.88 (95% confidence interval
1.49 to 2.36, p<0.0001) (Table 9).
Perioperative MortaIity
Overall thiq-day in-hospital mortality for patients in the administrative database was
1.5% (Table 8). In the univariate analysis, the odds ratio for death in women compared to
men was 0.85 (95 percent confidence interval, 0.64 to 1.12, P=0.3 1) (Table 8). Even after
adjustrnent for age and other risk factors, women were no more likeIy than men to
expenence in-hospital mortality (odds ratio 0.86, 95 percent confidence interval 0.64 to
1.18, P=0.36) (Table 8). In the logistic regression analysis, age greater than seventy years.
higher Charlson-Deyo scores, and surgery at a low-volume institution were significant
predictors of in-hospital death (Table 13).
Length of Stay
Overaii, the mean length of stay was 11.8 days, and this decreased with time (14.8 days in
1983 to 7.7 days in 1994, p<O.OOl). The mean length of stay was nearly one day lonser
for women than for men, even after adjustment for age. admission source, cornorbidity and
year of admission (1 2.4 days versus 1 1 -4 days. p=O.O 1 7). Twenty percent of patients had
an extended length of stay, defined as longer than fourteen days. The proportion of
patients with an extended length of stay decreased with time (3 1% in 1982 versus 9% in
1994, P<O.00 1) (Figure 6) . Women were more likeiy than men to have an extended
length of stay (odds ratio 1.17. 95% confidence interval 1 .O7 to 1.78, P<O.OOl) (Table 8).
M e r adjustment for age, year of procedure, admission source and comorbid conditions,
the odds of an extended length of stay for women was 1.20 (95% confidence interval 1.09
to 1.3 1. P-0.0001) (Table 8). Other predictors of an extended length of stay were age
over seventy, admission fiom an institution, higher Charlson-Deyo scores, and surgery at a
low-volume institution (Table 14)-
Other In-Hospital Morbidity
There was no significant difference in the risk of stroke, rnyocardial infàrction. congestive
heart failure, or any complication in women and men (Table 8). However, women were
more likely than men to have a complication coded as the most responsible diagosis for
the admission, with an odds ratio of 1.60 (95% confidence interval, 1.06 to 2.43, P=0.02)
(Table 8).
42 .2 Clinical Trial Database
Penoperative Stroke or Death
The overail incidence of penoperative stroke or death for patients in the clinical trial
database was 6.3%. In the univariate analysis. there was no significant dflerence in the
risk of perioperative stroke or death in women and men (odds ratio 1.22, 95% confidence
interval 0.70 to 2.13, P=0.49) (Table 15. Figure 7). M e r adjustment for age and other
nsk factors, the odds ratio for surgical stroke or death in women compared to men was
still not statisticaily significant (1 -34, 95% confidence interval 0.75 to 2.3 8. P=O.3 2)
(Table 15). In the regression analysis. the ody significant predictors of surgical stroke or
death were a history of myocardid infarction, lack of anticoagulation during surgery, use
of prhary rather than patch artenotomy closure and contralateral carotid artery occlusion
(Table 16).
Perioperative Stroke
The overaü risk of perioperative stroke was 6%. In the univanate analysis. there was no
signincant difEerence in the risk of penoperative stroke in women compared to men (odds
ratio 1.22, 95% codidence interval 0.69 to 2.17, P=0.57) (Table 15). M e r adjustrnent
for age and other nsk factors, the odds ratio for surgicd stroke in women compared to
men was not statistically significant (1.35. 95% confidence interval, 0.75 to 2.43, P=0.50)
(Table 15). ui the regression analysis, no clinical factors were found to be predictive of
perioperative stroke, although there was a trend towards increased events in patients with
contratateral carotid occlusion.
Perioperative Deat h
The overall incidence of penoperative death was 0.8%. There was no significant
difEerence in the nsk of surgical death in men and women (odds ratio 1.14, 95%
confidence interva1 0.28 to 8.78, P=0.91) (Table 15). Four of seven (57%) perioperative
deaths were stroke-related. In the regression analysis, the only significant clinical
predictor of surgicd death was a history of myocardial infarction; because of the small
number of outcome events, the confidence interval was quite wide.
Other Perioperative Outcomes
There were no sex dserences in either the unadjusted or adjusted risk of the combined
endpoint of perioperative death, stroke or rnyocardial infàrction, of major stroke, or of
local surgical complications such as cranial nerve palsy, hematoma, and infection (Table
15).
One-Year Outcomes in the Clinical Trial Database
At one year, both women and men assigned to surgicd therapy had a significant decrease
in the nsk of stroke or death compared to those assigned to medicd therapy (Table 17.
Figure 8). For any ipsiiaterd stroke or surgicai death, the nsk with surgical therapy
compared to medical therapy was 6% versus 12% (P<O.OO 1). For any stroke or death the
nsk with surgical therapy compared to rnedicd therapy was 1 I % versus 15% (P=0.0 16).
The nsk of stroke or death at one year was not significantly different in men and wornen in
either the medical or the surgical treatment groups (Table 18, Figure 9).
TABLE 1: S t J % i , , i ~ OF RISK FAC~ORS FOR PERIOPE~TWE COMPLICATIONS FROM CAROTID SLRCERY
Risk Factor Increased Riskt* Shrdy Design
FemaIe sex No RCT, rnulticenter chart audit, case series ' 'O-' "-' ' Yes RCT, meta-anaiysis, case s a i e ~ ' ~ " ~ ' - ' ~
Advanced age No RCT, multicenter chart audit, case seriesg9.' ' '.' ' --' IS
Yes ~eta-analysis'
H-vertension No RCT, case series ' '*" " Yes RCT, meta-analysis ' ~ 9
Diabetes meHitus No Meta-analysis, case series ' .' " Yes RCT 99.1 08.1 1 0
RCT. meta-ana1';sis. multicenter chart audit199" 'O-"- Multicenter chart auditg'
Srnobg No RCT, rneta-analysis, case se rie^'-"^^' "
S-vrnptomatic carotid Yes Meta-analysis, case se rie^'^^-'^^ stenosis No R C T ' O ~
Previous hernisphertc Yes stroke
RCT. case se rie^^.'^'
Marction on CT Yes RCT, case se rie^^^-'^^ NO R C T " ~
Contralaterai caro tid Yes RCT, r n r ~ - a n a ~ ~ s i s ' ~ ~ ~ ' ~ - ' I o
occlusion No Multicenter chart audit' ' - Ipsilateral carotid Yes RCT 99
ulceration No Multicenter chart audit' ' - No perioperative ASA Yes RCT"
Generai anesthesia (vs. Yes local)
Prirnary artetid Yes closure (vs. patch)
Meta-analysis. mutticenter chart auditg1-' ''
Surgery on the left Yes RCT'~ carotid arten;
Surg- at a low- Yes Mu1 ticenter chart auditg' volume institution *Mapitude of risk is not presented because of variations in data analysis arnongst studies
-
Administrative Database Ciinical Trial Database
Quai@hg S:mptoms
Timing of Symptoms
% Stenosis
Exctusion Criteria
Coîntsrvmtions
Prhary Outcome
Secondary Outcornes
Administrative database
Death or institutionalization
Deatb lnstitutionalization Exti-nded length of stay Other surgical complications Complication as most responsibIe diagosis
Stroke, TIA. or amaurosis figay
ASA
Death or stroke
Death Stroke Major stroke Death or major stroke Myocardial infarction Death, stroke or MI Other surgical complications Stroke or death at one year *
Abbreviations: RCT=randomized controlled trial; MI=rnyocardiai infarction: + = good; * = excellent
TABLE 3: CODXNG OF COMORBIDITY Ih' THE ADMI~TsTRATIVE DAT.~ASE
DiagoosW ICD-9-CM Charlson- Deyo Score
Myocardiai infarction 410,412 I Congestive heart failure 428 1 Peripheral vascdar disease 433-9-44 1,785.4, V43.3 1 Cerebrovascuiar dise= 430-438 1 Dementia 290 1 C hronic puhonary disease 490-496,500-505.506.4 1 Rbeumatologic disease 710.0,710.1,710.4,714.0-714.2-7 14.81.725 1 Pep tic ulcer disease 53 1-534 I Miid liver disease 571.2,57f.5,571.6.571.4 1 Diabetes 250.0-250.3,250.7 1 Diabetes with chronic complications 25a.4-250.6 3 Hemiplegia or parapIegia 344.1.342 - 7
Rend disease 582,583-0-583.7,585,586,588 LI 7
Mdignancy 140- 172-9, 174- 195.8.200-208.9 2 Moderate or severe liver disease 572.2-572.8 3 Metastatic solid tumour 1 96- 199.1 6 AIDS* 042-044.9 6
*On& coded d e r 1987
.. - - -
TABLE 4: COVXRUTES FOR THE ADMINISI-UTIVE DATABASE
Variable Coding
Age > 70 N d , Y-1 Ses Male+, Fernale= 1 Admission source Horne=€). O ther= 1 Year of suqery Continuous CharIson-Deyo score Continuous Hi&-volume institution N d , Y e ~ l
TABLE 5: COVARUTES FOR THE CLIEIICiU TRIALS DATABASE
Variable Coding
Age* Continuous ~ ~ e ' * Continuous Sex* Carotid stenosis (%) Contralateral carotid artery occlusion* Myocardial infarction* Angina Diabetes meiiitus Hymension Lipid l o w m g medications Peripheral vascular disease Smoking Stroke at en- Gaeral anesthetic d Anticoagulation useci during surgeq* Shunt used during surgexy Patch arteriotorny closure used*
Male+, Fernale= i Continuous N d , Yes=l N d , y-1 N o e , Y e i N A . Yes=l No*. Y e s l I N d . Yes=l NO*. Y--I No-=, Y e ~ l No*, Yes= 1 N d . Yes=I N d . Yes=l No-==. Y== 1 Nad. Yes= 1
Source of data NASCET=O. ECST=I
TABLE 6: BASELME CHARACTERISTICS OF WO~IEX AND MEN IK THE ALMI NISTR~TIVE DAT--.SE
Age (mean-years)
Age > 70 years (%)
Admitted îiom home (%)
Charlson cornorbidie score 4 (%)
Coron- a ~ q disease (%)
Congestive heart failure (%)
Chronic pulrnonacy disease (%)
Cancer (%)
Diabetes (%)
Hemi/paraplegia (%)
Peripheral vascutar disease (%)
Renal disease (%)
Dementla (%)
Arthritis (%)
Peptic ulcer disease (%)
Two or more comorbid conditions (%)
S u r g q at a low-volume institution
WOMEN @+341)
66
36
93
76
4
1
4
1
11
1
6
1
O
O
O
5
9%
MEN (~8 ,408)
66
3 6
94
73 *
6 ' * *
1
5 * *
1
1 0
1
7
O
O
O
O
6 *
8%
Women Men (n=506) (n=l 140)
Ags (mean-years) 63 6 3
Contralateral occlusion (%) 3 6
Angina (%)
Diabetes meIlitus (%)
Hypertension (%)
Lipid lowering medications (%) 5 4
Cigarette smoking (%) 38 34
Stroke at entry (%) 37 40
General anesthetic used (%) 96 96
EEG monitoring during surgery (%) 42 43
Anticoaplation during surgay (%)
Shunt used during surgq (%)
Patch used for arteriotorny closure (%)
Womea Men Unadjusted Odds Adjusted Odds Ratio (95% Cf) Ratio
(95% CI)
(adrnitted fiom home)
Death* or institutionalkation (any admission source)
Institutionaiization (admitteci ~ o m home)
lnsûtutionalization (an? admission source)
Myocardiai infarction
Death-, institutionalization or myocardiai infarction
An? complication (excluding death and institutionalization)
Complication coded as rnost responsible diagnosis
- CI=confidence intervai
-Death defmed as in-hospital thirty-day monality *P4).05, **P4.00 I
TABLE 9: DISCHARCE DESTINATION OF WOE~EK MEX INITLULY ADMITTED FROM HOME IS THE A D ~ ~ S T R A T ~ V E DATABASE
Discharge Destination Womea Men Unadjusted Odds Ratio Adjusted Odds Ratio (95% CI) (95% Cl)
Home 93% 95% 0.62 (0.53,0.73) 0.63 (0.53.0.73) t *
Home or home care 96% 97% 0.72 (0.58,0.89) 0.74 (0.60.0.92) *
Home care 3 -5% 2% 1.85 ( 1.47,2.32) 1.88 (1.49-2.36) **
Rehabilitation hospital 1.5% 1% 1.60 (1.15,2.24) 1 -62 j 1.16.2.37) *
Chronic care facilin 0.6% 0.4% 1-40 (0.83,2.39) 1.44 (0.84.2.15)
Acute care hospital 1% 1% 1.15 (0.76, 1.72) 1. i 4 (0.76, 1.72)
Other institution 0.7% 0.5% 1.32 (0.82,2,13) 1.25 (0.77.2.02)
TABLE 10: REGRESSION MODEL FOR DEATH OR DISCHARCET0 ~sTITuTIONAL CARE (IF ADJIITTED FROM HOME) I,V PATIE~TS LY THE A D ~ ~ I ~ ~ s T R A T ~ T DATAE~ASE
Variable $-Coefficient (S.E.) Wald df R Odds Ratio Significance (95% CI)
-
Fernale ses O. 18 (0.09) 3.98 1 0.02lO 1.19 (1.00-1-31] 0.05
Age over 70 0.61 (0.09) 47.80 1 0.1009 1.83(1.54,2.18) (0.0001
Charlson-Deyo score 0.24 (0.05) 25.38 1 0.0721 1.27 (1.16, 1-40) <0.0001
Low-volume institution 0.40 (O. 13) 8.09 1 0.0368 1.32 (1 -09. 1.85) 0.005
Yea. of surgerq. -0.04 (0.0 1 ) 12.23 1 -0.0477 0.96 (0.94.0.98) O .O005
Constant O. 17 (1 -03)
S.E.=standard error, Waid=Waid statistic ( ~ 2 distribution). dF-degrees of freedom &partial correlation coefficient. For model: Chi-square=97.64, si@cance<0.000 1. ~+.008
TABLE 11: =GRESSION MODEL FOR DEATH OR DISCHARGE TO ~ S I T ~ U T I O N A L C m ( R E G . W L E S S O F ADMISSION SOURCE) IN PATIENTS IN THE ADhlIMISTRTWE DATABASE
Variable $-Coefficient (S.E.) Wald df R Odds Ratio Significance (95% Cr)
.-------- Fernale ses 0.22 (0.08) 7.87 1 0.0324 1.25 ( 1 .07- 1.46) 0.005
Age over 70 0.60 (0.08) 59.20 1 O. I O 1 3 1-82 (1 .56,2.12) 4.000 1
C harlson-Deyo score 0.25 (0.04) 34.60 1 0.0765 1.29(1.18.1.40) <0.0001
Low-volume institution 0.38 (O. 12) 10.29 1 0.0385 1.47 (1.16, 1.86) 0.00 1
Year of surgery -0.04 (0.0 1 ) 16.90 1 -0.0517 0.96 (0.94,0.98) a.0001
Constant 0.77 (0.9 1 )
For modeI: Chi-square=l14.28, si~cançe<0.000 1. ~%.009
TABLE 12: REGRESSION MODEL FOR DISCHARGE TO ~sTITuTLONAL, CARE FOR PATIE~X~S ADhlITTED FROM HOME Ih' TEE ADMTNI!iXRATlVE DATABASE
Variable B-Coefficient (S.E.) Wald df R Odds Ratio Significance (95% CI)
Female ses 0.33 (0.1 1) 9.35 1 0.0470 1.39 (1-13-1.72) 0.002
Age over 70 0.70 (O. 1 1)
Charlson-Deyo score 0.1 9 (0.06) 9.96 1 0.0489 1 -2 1 (1 -08, 1.37) 0.002
Low-volume institution 0.28 (0.1 7) 2.75 1 0.0 150 1.32 (0.95. 1-85] 0.098
Consfant 0.25 ( 1 -26)
For model: Chi-sqwe=66.58, si@ùficanced).OOO 1. ~ 3 . 0 0 5
TABLE 13: REGRESSION MODEL FOR THIRTY-DAY IN-HOSPITAL MORT~UITY IN PATIENTS IN THE ADMINISTRATIVE DATABGSE
Variable j3-Coeficient (S.E.) Wald df R Odds Ratio Significance (95% CI)
Fernale sex -0.14 (O. 16) 0.84 1 0.0000 0.86(0.64, 1.18) 0.36
Age over 70 0.40 (0.15) 7.40 I 0.0523 1-50 (1 - 12.2.00) 0.006
Charlson-Deyo score 0.33 (0.07) 20.55 1 0.0969 1.40 (1.21, 1.61) ~0.0001
Low-volurne institution 0.59 (0.2 1) 7.76 1 0.0540 1.80 (1.19,2.72) 0.005
Y ear of -0.03 (0.02) 2.44 1 -0.0 150 0.97 (0.93. 1 .O 1 ) O. 12
Constant -1.73 (1-73)
For model: Chi-square=32.68, si&~cancd.OOO 1. ~ h . 0 0 3
TABLE 14: REGRESSION MODEL FOR ESTENDED LENGTH OF STAY (~11 DAYS) FOR PATIESTS IS THE ADhïINISTFUTn'E DATABASE
Variable -
p-Coenicient (S.E.) Wald df R Odds Ratio Signifïcance (95% CI)
Fmale Ses O. 18 (0.05) 13.72 1 0.0301 1~.20(1.09,1.31) 0.0002
Age over 70 0.28 (0.05) 35.85 1 0.0512 1.33 (1.21. 1.46) (0.000 I
Charlson-Deyo score 0-45 (0.03) 239.8 1 0.1357 1.57 (1.48- 1.66) 4.000 1
Year of surgeq -0.13 (0.01) 429.4 1 -0.18 0.87 (0.86,0.88) (0.000 1
Admitted fkom home -0.77 (0.08) 96.28 1 -0.0854 0.47 (0.4 1.0.55) ~0 .000 I
Constant 9.55 (0.56)
For model: Chi-squarc~816.85, signlncance4.000 1, ~'=0.06 1
TABLE 15: COMPAR~SON OF PEIUOPE~WTIVE MORBIDilT .%Ni MORT AL^ I S WOXIES X Y D MES 13 THE C~mrc;u. T u DATABASE
Women Men Unadjusted Odds Adjusted Odds Ratio Ratio (95% CI) (95% CI)
Parsimonious Full Model Model
Stroke or death 7% 6% 1.22 (0.70-2.13) 1-34 (0.75-2.38) 1-73 (0-85-3.501
Stroke 7% 6% 1 -22 (0.69-2.17) 1.35 (0.75-2.43) 1.59 (0.77-3.28)
Disabling or fatal stroke 4% 3% 1 -35 (0.6 1 -3 -00) 1.35 (0.6 1-3.00) 1.85 (0.724.78 i
My ocardia1 infarction 3 Oh 2% 1.29 (0.30-5.49) 1.44 (0.24-8.70) d a
Stroke. death or myocardial 8% 6% 1.3 1 (0.77-2.22) 1.47 (0.86-2.54) 1.90 (0.96-3.74) inîàrction
TABLE 16: REGRESSION MODEL (piU?!ij~lO!+i;I~~~) FOR THE COMBINED EVEP~T OF PERIOPER&T~F STROKE OR DEATR IN THE CLILL'ICAL TRIAL DATABASE
Variable $-Coefficient (S.E.) Wald df R Odds Ratio Siguificame (95% CI)
FemaIe ses 0.30 (0.29) 1 .O0 1 0.0000 1.34 (0.75-2.38) 0.33
AlF -0.36 (O. 18) 3.52 1 -0.0702 0.70 (0.49. 1 .O 1) 0.06
ConuaIatd occlusion 1-09 (0.48) 5.14 1 0.0870 3.97(1.16.7.61) 0.02
Previous myocardial 0.74 (0.3 3) 5.00 1 0.0851 2.10(1.10,4.03) 0.02 infarc tion
Patch clomire not used 0.6 1 (0.3 1) 3.96 1 0.0688 1.84 (1.01.333 0.05
Constant 10.77 (5.49)
For model: Chi-square= 19.6 1. significance4.0065, ~%.02 1
TABLE 17: COMPARESON OF MEDICAL M D SURGICAL THEwY AT OKE YEAR
Medical Therapy Surgical Therapy
Ipsilateral stroke or surgicd death (%) i 2 6 * *
Any siroke or death (%) IS 1 1 *
Major or disabling stroke (%) 13 8 *
Death (%) 3 3
*P<0.05, **P<O.OO 1
TABLE 1%: COMPAREON OF ONE-YEAR OUTCOMES OF WOMEK A i MEN IS THE CLINICAL TRLAL
DATABASE
Women Men Unadjusted Odds Adjusted Odds Ratio - Ratio (95% CI)
(95% CI)
Death 3% 4% 0.76 (0.41-1.41) 0.83 (0.44- 1.56)
Stroks 10% 10% 1.00 (0.71-1.41) 1 .O6 (0.75- 1
Stroke or death 12% 12% 1 .O0 (0.73- 1.37) 1.2 1 (0.78-1
Ipsilateral stroke or surpcal death 8% 9% 0.93 (0.77- 1-13) 1 .O3 (0.84- 1
Stroke or death in patients 10% 11% 1 .O2 (0.76-1.37) 1 -23 (0.82- 1.84) assïgned to surgical therapy
Sex
male --
fernale 83 84 85 86 87 88 89 90 91 92 93 94
Year
Year
FIGURE 3 : PROPORTION OF WOMEN LTNDERGOING SURGERY ObTR TIME
Year
i - Canadian population
FIGURE 3: PLOT OF AGE \ZRSUS PERCEhT STESOSIS
sex -- fernale - male
Sex - male -- fernale
Year
Day of study
sex --
fernale
male
P=0.49 for comparison
Day of study
P=0.003 for cornparison
260
Day of study
Treatment - - -
surgical
Treatment --
surgical
P=0.01 for cornparison
Day of study
P=0.63 for comparison
Sex - -
fernale
male
1 .O0
-90
-80
-70
-60
F~GURE 9, PANEL B: STROKE OR DEATH LN WOMEN .4ND h E N TRWTED W H ENDARTERECTO~~'
100 200 300 400
L -
\\ - L
O L
Day of study
1 .O0
P=0.64 for cornparison
.80 -
-70
-60
O i
100 200 300 400
-- L
Sex --
fernale
- male
CHAPTER IFIVE
DISCUSSION
nte objectives of this chpter m e toi
1. Discuss the mainfindÏngsj?otn the anaZysis;
2. List the major limitations of this stu@;
3. Discuss sec on^ fidings;
4. Outhe directions forfiture reseorch;
5. State the clinzcal implications of this SU+
5.1 Outcomes of surgery in women and men
In this study of patients undergoing carotid endarterectomy, the risk of an adverse
penoperative event was consistently higher in women than men. Compared to men.
women in the administrative database were 40% more likely to be institutionalized afler
surgery and were nearly 20% more likely to experience the combined endpoint of
institutionalization or in-hospitd death. Women were also more likely to have an
extended length of stay and to have a complication coded as the "most responsible
diagnosis" for the admission. In the clinical trial database, women were 35% more likely
to experience stroke and 34% more likely to experience the combined endpoint of
penoperative death or stroke, although the results were not statistically significant. These
findings are clinically relevant, given that a 20% to 40% increase in perioperative risks
could result in surgical complication rates that exceed current guidelines and negate the
62104 benefits of endmerectomy .
Despite increases in surgicd morbidity for women, short-tem mortality was similar in men
and women in both databases. One explanation for this finding is that the endpoints of
institutionaikation and prolonged length of stay may not be directly related to a patient's
nsk of dying. For example, it is possible that these endpoints reflect differences in social
supports for women, sex ditferences in routine postoperative care, or other issues
unrelated to surgical complications. An alternative explanation may be that women are at
higher risk of stroke-related mortality but that men are at higher risk of coronary-related
mortaiity. Thus, increases in stroke-related death in women are balanced by increases in
non-stro ke-related death in men.
This study also found that the increased risks for women, while important. are uniikely to
be extremely large. The administrative database analysis found that the combined risk of
death or institutionalization in women relative to men was probably less than 40%. Thus.
as long as surgical risks in men are less than about 4.3%. complication rates in women
would be expected to f d within the 6% complication rate recomrnended by current
guidelines. The increase in risk for women was smaller than that faced by patients with
other adverse indicators such as advanced age, more comorbid illness. or surgery at a low-
volume institution. Similarly. the clinical trial database analysis found that the observed
increased risks in women were smaller than those faced by patients with contralateral
occlusion or coronary artery disease. In addition, the analysis of one-year outcomes in
medical and surgical patients in the clinical trial database found that women and men
denved a s i d a r net benefit from surgery. suggesting that early increases in nsk may be
balanced by long-term benefits.
The observed early excesses in surgical morbidity for women are reminiscent of the
increased risks faced by women undergoing coronary artery by-pass surgery, and potential
explanations may be similar. In the coronary artery surgery Literature, much of the risk for
women is attributable to increased age, comorbidity and disease severity 3.4.126.13 t . In
contrast, the present andysis hvolved wornen and men undergoing carotid
endarterectc'my who had the same average age. Moreover, the distribution of major
comorbid iiiness (such as coronary artery disease and peripherai vascular disease) and
disease seventy (as measured by prior cerebrovascular syrnptoms, degree of stenosis. and
the presence of contralateral disease) was sirnilar. This suggests that there may be other
unmeasured factors associated with female sex that result in an increased nsk of surgical
complications.
A simple anatornic explanation is unlikely to fully account for our findings. Smaller body
size with, presurnably, smaller artenaI vasculature is a factor that has been associated with
penoperative complications in women during coronary bypass ~ u r ~ e r y ~ ~ ' * . Differences in
the relative size of carotid arteries in men and women are not welf documented in the
literature, but are unlikely to be substantial. Moreover, smaller anatomical size would be
expected to be relativeiy less important in larger sized blood vessels, such as carotid
arteries. Al1 of these factors suggest there is no simple explanation for the higher nsk of
perioperative events in women.
5 -2 Limitations
Although this study had sufficient power to exclude an extremely large increase in the
penoperative hazards in women compared to men, true estimates of the relative risks of
endarterectomy in women remain uncertain. There are a number of reasons why this study
did not provide a precise answer to the question of whether or not women are at higher
nsk of surgical complications than men. FirstIy, it is iikely that the administrative database
analysis underestimated stroke risks, since only those strokes severe enough to result in
death or institutionalization would have been included in the analysis. Secondly, although
the chical trial database analysis showed a trend in the direction of increased risks of
perioperative stroke or death in women, this anaiysis may also have underestimated the
nsks in women due to the srnail nurnber of women and the low incidence of complications.
Post-hoc power calculations suggest that a sample size of 1,200 patients (30% women)
would be required to demonstrate a 35% increase in the surgicai risks for women
cornpared to men. Ln addition, randomited trials often underestimate the toxicity of
treatment because they occur under ideal circumstances where dinicians and the heaith
care system have supplementary resources and where patients are prescreened and
excluded if substantial comorbidity is found In the face of these limitations, the tme
surgicai risks in women remain uncertain, and may be either higher or lower than those
found in this study.
Other important limitations relate to the study methodology. The administrative database
analysis suffered from many of the weaknesses common to any study involving a
secondary data source. First, coding inaccuracies rnay have resulted in the inappropriate
inclusion or exclusion of some endarterectomy patients; however, this is unlikely to have
resulted in any large systematic biases. The dataset included al1 endmerectomies. even
repeat procedures and those where other operations were performed during the same
admission. This may have resulted in some bias, and the direction is uncertain. Patients
who underwent a second endarterectomy may have been at lower nsk of penoperative
complications than unselected patients, while those who underwent endarterectorny at the
same time as a procedure such as coronary artery bypass grafting were at higher nsk of
complications.
A second senous Limitation was that secondary diagnoses might have been coded
incornpletely or inaccurately. The finding that most comorbid conditions were less
cornmon in the administrative database than in the clinical triai database (where patients
were carefùlly selected) suggesü that comorbidity was undercoded in the administrative
database. Many other important prognostic factors. such as pnor symptom status. degree
of carotid stenosis, contralaterd carotid occlusion, clinical risk factors and surgical details
were not present in the database. Those risk factors that were available were coded as
simple categories (disease present or absent) although disease severity rnay have greater
prognostic importance than the mere presence or absence of a diagnosis. Data on surgeon
and centre characteristics were unavailabIe, and the indications for endarterectomy were
unknown. No data on cointerventions were available, and it could not be determined
whether men and wornen were treated equally aside from endarterectomy. These
deficiencies rnay have resulted in an inadequate adjustment for baseline differences
between men and women, leading to an inaccurate risk-outcome association.
A third key Limitation of the administrative database was the inability to directly measure
perioperative complications. Thus, the analysis focussed on the proxy measure of
institutionalization, and led to some difficulties in the interpretation of outcome events.
Women were more lïkely than men to be institutionalized foliowing endarterectomy.
however, this study could not determine whether or not institutionalization was the result
of perioperative complications or whether it was a reflection of differences in social
supports or other factors unrelated to surgery. SVnilar limitations appiy to the
interpretation of length of stay in women and men.
Other limitations of the administrative database analysis were the lack of information on
long term outcomes and events occumng after discharge fiom hospital. Only in-hospital
rnortality was captured in the database; since length of stay was longer in women. this
could have led to an overestimation of mortality nsks in women compared to men. In
addition, the results may be çeneralizable to patients in Ontario but may not necessarily
refiect outcomes in areas with difTerent practice patterns or health care policies. It is also
possible that advances in surgicd techniques and medical therapy have resulted in changes
in surgical nsks so that this analysis of data fiom 1982 to 1994 no longer reflects current
standards of practice. Examples of changes in practice patterns that may have altered
surgical nsks include the more f?equent use of local anesthesia, patch artenotomy closure,
and routine perioperative antiplatelet therapy.
The analysis of the clinical trial database suffered fiom the inherent limitations of subgroup
analyses. Most imporîantly, the analysis lacked the power to exclude small but potentially
important sex differences in perioperative risks. Other limitations of subgroup analyses.
such as multiple cornparisons, improper subgroups and data dredging were Iess of a
concem in this study. Although the subgroups of men and women were not specified at
the start of the clinical trials, they were defined prior to the secondary data analysis, and
were not data-derived. Moreover, the single hypothesis was proposed based on existing
data and biological plausibiiity prior to data analysis. In addition, penoperative stroke and
death were primary endpoints in the original trials; hence, prospectively collected data
were availabie for the outcome of interest.
Other limitations of the clinical trial database anaiysis relate to the coding of secondary
diagnoses and cointerventions. While valid data were available on the presence or absence
of many important clinical and surgical variables, information on other potential
confounders was lacking. For example, data on body size and carotid artery diameter
were not available in the database. A fùrther limitation was the use of the pooled
database, since some differences existed in the distribution of baseline characteristics of
the study patients, as well as in the coding of specific outcome measures. However. this
was unlikely to have led to any bias in the detection of events in women compared to men,
and had the advantage of increasing the available sample size. In addition, the finding of
consistent results in the two studies lent strength to the subgroup analysis.
Additional study limitations relate to the statistical methods, particularly the use of logistic
regression 167.168.170.171 . It is likely that the regression models did not adjust for al1
comorbid conditions or confounders, especially in the administrative database. In the
clinical triai database, the s m d number of perioperative events relative to the number of
predictor variables may have contributed to an unreliable risk assessment. The risk
estimates were associated with wide confidence intervais, suggestkg ovefining;
underfitting rnay also have occurred due to the omission of important variables from the
model. Additionafly, many interaction terms were not examined, again because of the risk
of overfïtting, and variables were not tested for coüinearity. Finally. the regression models
were not validated, so the stability of the coefficients and the predictive ability of the
models are unknown.
5.3 Long-Term Outcomes in Women and Men
This study found that women treated medically had one-year stroke nsks that were
comparable to those of men, and that endarterectomy resulted in a significant reduction in
the one-year risk of stroke and death in both men and women. This finding conflicts with
recent data on patients with rnoderate (50% to 69%) stenosis, where women did not
denve a net benefit fiom endarterectomy primarily because oflow recurrent stroke nsks in
those treated with medical therapy Il9. This discrepancy in results may reflect the higher
stroke nsks in women with severe stenosis, other unmeasured differences in the patient
populations, or inaccurate risk assessments in the subgroup analyses.
5.3 Predictors of surgicai complications
Contralateral occlusion and coronary artery disease were predictive of surgical
complications in the clinical trial database whereas advanced age and comorbidity were
prediaive of complications in the administrative database. However, these clinical factors
accounted for only a smaii proportion of surgical risks, suggesting that other baseline
patient factors or unmeasured technical or surgeon-related factors may be more important
in prediaing adverse outcomes. The substantially higher perioperative complication rates
observed at low-volume institutions, in particular, emphasize the role of surgical factors in
predicting risks. If higher surgical risks in women are related to technical factors. it is
possible that some surgeons, with more expenence operating on female patients. will
achieve lower perioperative complication rates in women. However, the precise role of
surgical factors in the modification of adverse perioperative events in women is unhown.
5.4 Baseline characteristics
An unanticipated finding in both the administrative and clinical database analyses was that
men and women had the same average age at the tirne of surgery. Previous studies have
shown that women develop syrnptornatic cerebrovascular disease and carotid stenosis later
than men, and tend to be several years oider than men at the time of coronary and
penpherd revascul~zation U.5.10.23.59.60.133-U6.139 - Based on this data., one would have
anticipated that women undergoing endarterectorny would be older than men. It is
unlikely that this sidarity in average age at time of surgery is a reflection of hitherto
unrecognized biological sisnilarities in the development of carotid atherosclerosis in
women and men. An alternative explanation is that older women were selectively
excluded fkom surgery, with a resultant lowering in the mean age of women undergoing
endart erectomy.
Some additional findhgs were consistent with the exclusion of elderly women from
surgery. First, the proportion of women undergoing surgery was the same in every age
group, despite strikùig increases in the proportion of women in the general population in
the older age categories. For example, although women constituted more than sw percent of the Canadian population over the age of seventy-five, ody thirty percent of the
patients undergoing endarterectomy in this age group were womenl". Second. despite
increases in the proportion of elderly patients receivhg endarterectomy d e r 199 1. the
proportion of women undergoing surgery remained constant over tirne. Again, since
women constitute a greater proportion of the elderly population with cerebrovascular
disease, a concomitant increase in the proportion of women undergoing surgery might
have been expected. Another indication of the exclusion of older women fkom surgery
might have been a lesser degree of carotid stenosis in the remaining, relatively younger.
women in the study, since the severity of carotid stenosis increases with age. However. the
analysis of stenosis by age and sex revealed no significant differences between the degee
of stenosis in men and women at any age, and also no strong association between age and
percent stenosis. Further research is needed to explain the age similarity in women and
men.
5 -5 Future Research
Further research into the relative nsks of surgery in men and women is needed, preferably
using data fiom other trials of carotid endarterectomy, as well as other data sources.
Specifically, the clinical trial database anaiysis could be extended to include NASCET
patients with 50% to 69% stenosis. which would greatly increase the sample size and
permit the detection of smail dserences in penoperative risks. The administrative
database could be linked with data fiom future hospital admissions, which would allow an
estimation of recurrent stroke nsks in men and women. Other study designs, such as a
meta-analysis of clinical triais of endarterectorny for both symptomatic and asymptomatic
disease, rnight aiso yield useful information. Animal experiments might permit an
evaluation of different surgicai techniques and cointerventions, but are unlikely to provide
any definitive answers to the question of sex daerences in surgical risks.
This study did not evaluate the reasons for daerences in surgicd risks in men and women,
and it remains uncertain whether the dzerences are due to baseline patient factors. or
whether modifications in surgical techniques or medical therapy can affect outcornes in
women. Further research is needed into the etiology and prevention of perioperative
complications in both men and women. Since a randomized trial of gender cannot be
done, future research in this area will likely be based on secondary analyses and secondary
data sources.
The intriguing finding that women and men are the same age at the time of surgery aiso
requires further analysis. At this tirne. it is not known whether this is a result of biological
sirnilarity in the development of disease. some bias in the selection of patients for surgery,
or some other factor. Similarly. the low rates of surgery in women relative to men rernain
unexplained. In order to explore this fûrther, studies of the prevalence of carotid stenosis
in women and men with symptomatic cerebrovascular disease are needed, as are studies of
sex dif5erences in the indications and contraindications to carotid endarterectomy.
5.6 Clinical Implications
This study found that women undergohg carotid endarterectomy were at higher risk of
selected penoperative events than men. At one year, however, women seemed to derive a
net benefit eom endarterectomy comparable to that of men. This suggests that women
should not be discouraged nom surgery solely on the basis of surgical risks; indeed.
surgey rnay be underutilized in women. Such potential underutilization does not appear
to be justified by either markedly higher penoperative risks or markedly lower net benefits
in women.
The results of this study rnay serve to stimulate funher research into the prevention of
surgical complications. Moreover, the findings may encourage the referral of both women
and men to qualiIied surgeons with acceptable sex-specific perioperative complication
rates. The findings of this study should not be used to exclude women fiom
endarterectomy or to encourage surgeons to avoid women in order to enhance their
surgical statistics. Effons to monitor quality of care should not create perverse incentives
that compromise access for sick patients.
5 -7 Final Conclusions
Perhaps the most noteworthy incidental finding was that carotid endarterectomy was
performed twice as often in men as in women. This finding was large, statistically
significant, and consistent in both the administrative and clinical trial databases.
Moreover, other studies have documented sirnilar sex gradients in endmerectomy
rateSn97.98. 173 - A plausible explanation for this finding is that endarterectomy is
undenitilized in women. Further research is needed into the patient, physician and societal
factors that may limit wornen's access to carotid surgery.
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