Sex-Related Differences in Quality of Care and Short-Term Mortality Among Patients With Acute Stroke in Denmark
A Nationwide Follow-Up Study
Background and Purpose— Sex may predict level of care and successive outcome among patients with stroke. We examined fulfillment of quality of care criteria according to sex and possible impact of any sex-related differences on short-term mortality in a population-based nationwide follow-up study in Denmark.
Methods— We identified 29 549 patients admitted with stroke between January 2003 and October 2005 in the Danish National Indicator Project. Data on 30- and 90-day mortality were obtained from The Civil Registration System. We compared proportions of patients receiving adequate care between sexes, as measured by admission to a specialized stroke unit, administration of antiplatelet or anticoagulant therapy, examination with CT/MRI scan, and assessment by a physiotherapist, an occupational therapist, and of nutritional risk. Further, we computed 30- and 90-day mortality rate ratios (MRR), adjusted for patient characteristics, fulfillment of quality of care criteria, and department.
Results— The proportion of patients who received adequate care was either slightly lower or similar among women when compared to men. The relative risks (RR) of receiving specific components of care ranged from 0.84 (95% confidence interval [CI]:0.74 to 0.96) to 1.01 (95% CI:0.96 to 1.06) when comparing sexes. The adjusted mortality rate ratios were lower among women and adjustment for fulfillment of quality of care criteria had only marginal impact.
Conclusions— There appear not to be any substantial sex-related differences in acute hospital care among patients with stroke in Denmark. The lower female short-term mortality is therefore most likely explained by other factors.
Stroke is a leading cause of mortality among both women and men.1 Although this disease has many similarities in women and men, a growing body of evidence indicates that differences may exist in treatment, outcome, and prognosis of stroke between sexes.2–5 Such a pattern has also been reported among other disease entities, in particular among patients with coronary heart disease and congestive heart failure.6 Existing literature on stroke,2–5 although not all,7 suggests that women receive fewer relevant evidence-based diagnostic examinations and less care than men. Uncertainty remains, however, about the magnitude and implications for the outcomes of stroke of these possible sex-related differences. There seems to be a growing need for a better understanding of sex differences in both presentation, progression, treatment, and outcome of stroke.8 Also, existing literature suggest that older patients, typically starting from age 65 years, seem to receive fewer relevant evidence-based diagnostic examinations and less care,9–11 however few studies investigating sex differences in treatment and outcome have investigated whether the observed differences can in fact be contributed to age- rather than sex-related differences given the higher mean age of female stroke patients. Also, only few studies had detailed data on diagnosis and care (in particular, the timing of specific interventions) and complete follow-up. Furthermore, none of these studies have examined to which extent the possible differences in the quality of care could have an impact on sex-related differences in mortality.
We aimed to explore whether sex-related differences in care still occur after stratifying by age, and to assess whether they affect short-term mortality. We therefore examined the quality of care and mortality according to sex in a nationwide population-based follow-up study of Danish patients with stroke.
The Danish National Indicator Project (DNIP)
The Danish National Health Service provides tax-supported health care to the country’s 5 million residents, all of whom have free access to hospital care. DNIP is a nationwide initiative to monitor and improve the quality of care for specific diseases, including stroke.12 The project does this by developing evidence-based quality criteria related to the structure, process, and outcome of health care and, subsequently, by monitoring the fulfillment of these criteria. Participation in the project is mandatory for all hospital departments in Denmark treating patients with acute stroke.
We identified all admissions with acute stroke registered in DNIP from January 13, 2003 to November 1, 2005 (n=31 157 from 41 hospital departments). All patients (≥18 years) admitted to Danish hospitals with acute stroke according to the WHO criteria (ie, rapidly developed clinical signs of focal or global disturbance of cerebral function, lasting more than 24 hours or until death, with no apparent nonvascular cause13) are eligible for inclusion in DNIP. Patients with subdural hematoma, epidural or subarachnoidal hemorrhage, retinal infarct, and infarct caused by, trauma, infection, surgery, or an intracerebral malign process are not included. For this study we only included the first stroke event registered during the study period. Furthermore, only patients with a valid civil registry number (a unique personal identification number allowing unambiguous linkage between public registers) residing in Denmark and therefore eligible for follow-up were included. A total of 29 549 patients (94.8% of the original patient population) were included.
Quality of Care Criteria
A national expert panel including physicians, nurses, physiotherapists, and occupational therapists identified 7 quality of care criteria covering the acute phase of stroke based on systematic search of the scientific literature.12 In the selection of the criteria, the feasibility of collecting the required data in routine clinical settings and the ability of the criteria to reflect the multidisciplinary efforts involved in modern stroke care were also considered. The criteria included early admission to a specialized stroke unit, early administration of antiplatelet or anticoagulant therapy, early examination with CT/MRI scan, and early assessment by a physiotherapist, an occupational therapist, and of nutritional risk.
A time frame was defined for each criterion to capture the timeliness of the interventions. The time frame was the second day of hospitalization for all criteria, except initiation of oral anticoagulant therapy where the time frame was the 14th day of hospitalization. The time frames were in accordance with the principles of the official Danish guidelines for early management of patients with stroke issued by the National Board of Health.14 The time frames were based on the available scientific evidence which included large scale clinical trials for early administration of antiplatelet therapy but consensus agreement among experts for most of the other processes of care.15–17
A specialized stroke unit was defined as a hospital department/unit that exclusively or primarily is dedicated to patients with stroke and which is characterized by multidisciplinary teams, a staff with a specific interest in stroke, involvement of relatives, and continuous education of the staff. Administration of antiplatelet and oral anticoagulant therapy was defined as continuous use of the drugs and not merely a single dose. Assessment by a physiotherapist and occupational therapist was defined as a formal bed-side assessment of the patient’s need of rehabilitation, whereas assessment of nutritional risk was defined as an assessment after the recommendations of the European Society for Parenteral and Enteral Nutrition, ie, calculation of a score which both accounts for the nutritional status and for the stress induced by the stroke.18
On hospital admission, data on care, and patient characteristics were collected for each patient using a standardized form. After hospital discharge the data were entered into a central database. Patients were classified as eligible or noneligible for the specific processes of care depending on whether the stroke team or physician treating the patient identified contraindications, eg, severe dementia in a patient with ischemic stroke and atrial fibrillation precluding oral anticoagulant therapy, or rapid spontaneous recovery of motor symptoms making early assessment by a physiotherapist and occupational therapist irrelevant. Detailed written instructions were available to the staff which specified criteria for deeming a patient ineligible for the care processes. The reason for deeming a specific patient ineligible was not recorded in the database.
At the time of hospital admission, data were collected on the following characteristics: age, sex, marital status (living with partner, family or friend, living alone), housing (own home, nursing home or other form of institution), Scandinavian Stroke Scale score, history of stroke or myocardial infarction, previous or current atrial fibrillation, hypertension, diabetes mellitus or intermittant claudication, smoking habits (smoker, ex-smoker, never), and alcohol intake (≤14/21, >14/21 drinks per week for women and men, respectively).
We also computed the Charlson comorbidity index score for each patient based on all discharge diagnoses recorded before the stroke hospitalization. The Charlson comorbidity index covers 19 major disease categories, including congestive heart failure, renal disease, and cancer, weighted according to their prognostic impact on patient survival.19 The index has previously been adapted for use with hospital discharge registry data and has been reported to be useful also among patients with stroke.20,21 We defined three levels of comorbidity for each patient, based on their complete hospital discharge history, as follows: 0 comorbidities (“none”), 1 to 2 comorbidities (“low”), and >2 comorbidities (“high”). Data on previous hospitalizations were obtained from The National Registry of Patients, which contains data on all discharges from all nonpsychiatric hospitals in Denmark since 1977.
Scandinavian Stroke Scale was used to assess admission stroke severity. The scale is a validated and widely used neurological stroke scale in Scandinavia that evaluates level of consciousness; eye movement; power in the arm, hand, and leg; orientation; aphasia; facial paresis; and gait on a total score that ranges from 0 to 58.22,23
We computed 30- and 90-day mortality using information from the Civil Registration System. This registry, which is updated daily, keeps electronic records on vital status (dead or alive), date of death, and residence of all Danish citizens. Since 1968, all Danish residents have been assigned a unique civil registration number, which is used in all health databases and permits unambiguous record linkage.24
We compared the distribution of patient characteristics between women and men by chi-squared test. To evaluate the quality of care we first calculated, for each sex, the proportion of patients receiving adequate care, both defined as fulfillment of the specific quality of care criteria and as proportion of fulfilled criteria that the patient was deemed eligible for (<50%, 50% to 99% and 100%). Further, we stratified the patients according to age (≤65, >65 to 80 and >80 years) attributable to the sex-specific differences in age distribution and previous reports of age-related differences in care among patients with stroke.2–4,9–11 The proportions were compared using male sex as reference, and relative risks (RR) were computed for each age group. Secondly, we computed 30-and 90-day mortality rates according to sex. We used Cox proportional hazards regression to obtain mortality rate ratios (MRR) for time to death within 30 or 90 days after stroke, according to sex, while adjusting for potential confounders of the association between sex and mortality ie, patient characteristics, department, and fulfillment of quality of care criteria. Follow-up time started on the date of hospital admission for stroke and ended on date of death, emigration, or after 30 (or 90) days, whichever came first. We corrected for possible clustering by department in all mortality analyses as unmeasured characteristics of the department, including other aspects of quality of care than the criteria examined in this study, might be associated with patient mortality. If this is the case, the mortality of patients treated at the same department is necessarily correlated and conventional statistical analyses may be invalidated. We first computed the unadjusted MRRs according to sex, followed by adjustment for patient characteristics and department and finally additionally adjusted for proportion of fulfilled quality of care criteria that each patient was deemed eligible for. We analyzed data using STATA version 9.0 (StataCorp).
Table 1 shows characteristics of the 29 549 patients according to sex. Female sex was associated with higher proportions of older patients, atrial fibrillation, hypertension, severe strokes, care home residency, and more women than men were living alone. Male sex was associated with higher proportions of diabetes, myocardial infarction, former strokes, intermittant claudication, high alcohol intake, and daily smoking. We found no statistical significant differences in the distribution of the Charlson comorbidity index score between women and men.
Fulfillment of Quality of Care Criteria
Table 2 displays, according to sex and stratified by age, the proportions of patients which fulfilled the quality of care criteria. The varying number of patients included in the analysis of the specific criteria reflect that a varying proportion of the patients was eligible to the individual criteria, eg, in 2196 female patients aged 65 years or younger platelet inhibitor therapy was considered to be indicated as the patients had an ischemic or unspecified stroke and no contraindications for platelet inhibitory therapy, and of these, 1657 received the treatment within 2 days after hospitalization (75.5%). There were no major differences in the proportion of men and women deemed ineligible or with missing data for the specific quality of care criteria. In general, the differences were less than 1% for each of the indicators (data not shown). The proportion of eligible patients who fulfilled the quality of care criteria was slightly lower for women compared with men for most of the criteria (ie, the RRs ranged from 0.84 [95% confidence interval (CI): 0.74 to 0.96] to 1.01 [95% CI:0.96 to 1.06]). The largest difference was found for oral anticoagulant therapy. However, the RR remained above 0.90 for all quality of care criteria, except for oral anticoagulant therapy among patients aged ≤65 years (RR=0.84, 95% CI:0.69 to 1.03) and >80 years (RR=0.84, 95% CI:0.74 to 0.96).
The modest differences in quality of care remained when we compared the proportion of fulfilled quality of care criteria that each patient was deemed eligible for between women and men. The largest difference was found among patients aged between >65 and ≤80 years where the RR of fulfilling 100% of the criteria was 0.90 (95% CI:0.85 to 0.96) when comparing women with men. For patients ≤65 years and >80 years the corresponding RRs were 0.99 (0.92 to 1.06) and 0.94 (0.86 to 1.02), respectively.
30- and 90-Day Cumulative Mortality
The overall cumulative 30- and 90-day mortality was 12.8% and 17.4% for women and 9.7% and 12.9% for men, respectively. The corresponding overall crude MRRs were 1.34 (95% CI:1.26 to 1.44) after 30 days and 1.38 (95% CI:1.30 to 1.46) after 90 days. As expected, we found a reduction of the MRRs after adjustment for patient characteristics, including sociodemographic and clinical characteristics. The adjusted MRRs were 0.79 (95% CI: 0.73 to 0.86) after 30 days and 0.81 (95% CI: 0.75 to 0.87) after 90 days. Further adjustment for differences in the proportion of fulfilled quality of care criteria had only a marginal impact on the adjusted MRRs (ie, the fully adjusted MRRs were 0.79 (95% CI 0.72 to 0.86) for 30 days and 0.81 (95% CI 0.75 to 0.87) at 90 days). Stratifying the analyses according to age did not change this pattern (Table 3⇓). The survival advantage of female patients was also present when stratifying for age, in particular in the oldest age group for 30 day mortality (Table 3⇓).
In this large nationwide follow-up study, we observed no substantial sex-related differences in the quality of acute hospital care among patients with stroke when stratifying for age. Furthermore, short-term mortality appeared to be lower among women compared with men in particularly in the oldest age groups. Sex-related differences in mortality appeared not to be explained by differences in acute hospital care.
Strengths and Limitations
The main strength of our study is its prospective population-based design with complete long-term follow-up and consequently low risk of selection and information bias. Also, our analyses were based on a large cohort, with detailed data on a range of specific processes of care and only patients without contraindications for the specific processes of care were included in the analyses. Furthermore, while examining mortality, we reduced confounding by adjusting for a wide range of prognostic factors.
However the use of data collected in a nonstandardized setting during routine clinical work is a limitation, potentially affecting accuracy of collected data. At the same time, participation in DNIP is mandatory for all departments treating patients with acute stroke in Denmark, and extensive efforts are made to ensure the validity of DNIP.12 In particular, a yearly structured audit is conducted nationally, regionally, and locally, which includes validation of the completeness of patient registration against hospital discharge registries. The fact that the eligibility for the specific processes of care was determined by the staff might be a cause for concern as health professionals’ could prioritize differently. However, we found no differences in the proportion of women and men considered eligible for care.
Although we adjusted for a wide range of prognostic factors, we cannot entirely exclude the possibility that our results may still be influenced by residual confounding attributable to the use of crude variables (eg, data on levels of hypertension were not available) or unaccounted confounding from factors not included in the analyses (eg, mental function or diet). The prevalence of patients with missing data on the prognostic factors ranged between 5% and 30% for the variables considered. Although missing data should always be a reason for concern, we have no reason to believe that this had any substantial influence on our findings which remained virtually unchanged whether or not patients with missing data were included in the analyses.
We used mortality as the clinical outcome. Despite its obvious importance, mortality is certainly not the only outcome relevant for patients with stroke. Examination of the possible effect of sex-related differences in quality of care on other clinical outcomes (eg, functional level after discharge) is also of major interest. Unfortunately such data were not available in our study population. Because we only found minor sex-related differences in acute hospital care after stratifying for age, it seems less likely that the differences in quality of care could explain major sex-related differences in other outcomes. However, caution is needed before extrapolating our findings to functional level and other outcomes, which may be more sensitive outcome measures than mortality.
Comparison With Other Studies
Our findings regarding quality of care are in accordance with those observed in 2005 by Kapral et al7 in a study on 3323 patients in Canada. Among other things, this study found that there were no sex differences in the use of neuroimaging or antithrombotic therapy, and that after adjustment for age, women were as likely as men to receive care on an acute stroke unit. In our study, we also found no sex differences in the use of neuroimaging, admission to a specialized stroke unit, or antiplatelet therapy. However, our findings regarding quality of care differ from that of other studies, including three studies on patients with stroke and patients with other cardiovascular diseases including patients with coronary heart disease and congestive heart failure.2,3,5,6,25 In a large German study, Foerch et al found sex disparities in acute stroke management in terms of early hospital admission and thrombolytic treatment. This disparity only appeared among elderly stroke patients (patients above 74 years), and no imbalances were observed in the younger patients. Early hospital admission was defined as admission within the critical first 3 hours after symptom onset. Although, in our study, early admission to a specialized stroke unit was defined as admission no later than the second day of hospitalization, we found no differences between sexes in early hospital admission and only minor differences in antiplatelet therapy or oral anticoagulant therapy irrespective of age. In another prospective joint European study on 4499 patients by Di Carlo et al, found that brain imaging and other diagnostic tools were less frequently used among women, as only 77.1% of women received brain imaging compared with 87.7% of men. However, in our study we found no differences in the use of CT/MRI scans between sexes after stratifying for age.
The lower mortality among women in our study confirms findings from other studies on patients with stroke, including a previous study based on data from DNIP.26,27 The factors possibly underlying an improved survival among women could in theory include a more favorable prognostic patient profile (eg, less comorbidity), a more health-minded lifestyle (eg, less smoking, smaller alcohol intake, healthier diet, and more physical activity), better quality of care (including acute care, rehabilitation, and secondary prevention), or real physiological advantages compared with men. Our findings lend support to the hypothesis that women may have a physiological advantage when it comes to surviving a stroke as the better survival of women remained after taking differences in the prognostic profile, lifestyle, and quality of early care into account. Female sex hormones, in particular progesterone, are obvious candidates in the search for a physiological mechanism underlying the female survival advantage and a large and growing body of evidence, including a recently published pilot clinical trial, indeed indicates that progesterone exerts neuroprotective effects on the central nervous system.28 The neuroprotective effects appear to include protection of the blood-brain barrier, reduction in the development of cerebral edema, downregulation of the inflammatory cascade, and limitation of cellular necrosis and apoptosis.28
A central aspect in the struggle against sexism is to get a clearer picture of the extent and consequences of any sex-related differential treatment. In this context it is important to be aware that in some situations there could be sound ethical and clinical reasons for treating female patients different than male patients. Thus it is well known that female stroke patients generally are older than male stroke patients and therefore form a larger part of the oldest stroke population. Previous studies indicate that age-related differences in level of care exists among patients with stroke,9–11 and age therefore appears to be an important confounder when comparing sexes, which should always be accounted for when comparing performance measures in stroke populations. It is essential that studies of sex-related differences take these aspects into account, to avoid overestimating or misinterpreting the observed differences thus hindering the effort of effective elimination of true sexism.
In conclusion, we found only minor sex-related differences in acute hospital care among patients with stroke in Denmark when stratifying for age. The largest sex-related differences were found for early anticoagulant therapy; however, the differences were not substantial. Quality of early care did not appear to explain the observed sex-related differences in mortality.
Sources of Funding
This work was supported by grants from the Foundation for Research in Neurology and The Aarhus University Research Foundation.
- Received November 22, 2008.
- Accepted December 3, 2008.
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